Natural Product Reports: Themed Issue: Novel Antibiotics and Antimicrobial Resistance

Volume 34 Number 7 July 2017 Pages 679–934
Natural Product
Reports
rsc.li/npr
Themed issue: Novel Antibiotics and Antimicrobial Resistance

ISSN 0265-0568
REVIEW ARTICLE
G. L. Challis et al.
Antibiotics from Gram-negative bacteria: a comprehensive overview and
selected biosynthetic highlights
Natural Product
Reports
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Antibiotics from Gram-negative bacteria:

Cite this: Nat. Prod. Rep., 2017, 34, 712
a comprehensive overview and selected
biosynthetic highlights
J. Masschelein,† M. Jenner † and G. L. Challis *
Covering: up to 2017
The overwhelming majority of antibiotics in clinical use originate from Gram-positive Actinobacteria. In
recent years, however, Gram-negative bacteria have become increasingly recognised as a rich yet
underexplored source of novel antimicrobials, with the potential to combat the looming health threat
posed by antibiotic resistance. In this article, we have compiled a comprehensive list of natural products
Received 31st January 2017
with antimicrobial activity from Gram-negative bacteria, including information on their biosynthetic
origin(s) and molecular target(s), where known. We also provide a detailed discussion of several unusual
DOI: 10.1039/c7np00010c
pathways for antibiotic biosynthesis in Gram-negative bacteria, serving to highlight the exceptional
rsc.li/npr biocatalytic repertoire of this group of microorganisms.
1. Introduction 7. Conclusions and perspectives

2. Polyketides 8. Acknowledgements
2.1 Ambruticins and jerangolids 9. References
2.2 Gladiolin and etnangien
2.3 Mupirocin and the thiomarinols
2.4 Elansolids 1. Introduction
3. Nonribosomal peptides
3.1 Teixobactin Gram-negative bacteria are an enormous group of taxonomi-
3.2 Brabantamide A cally diverse and ubiquitous environmental bacteria, capable of
3.3 Ecteinascidin-743 thriving in practically every ecological niche on Earth. This
4. Hybrid polyketide-nonribosomal peptide natural versatility is reected in the wide variety of lifestyles and
products phenotypes exhibited by these organisms, ranging from rhizo-
4.1 Andrimid spheric nitrogen-xing bacteria and marine and terrestrial
4.2 Xenocoumacin endosymbionts, to psychrophilic bacteria from deep-sea envi-
4.3 Zeamines ronments and opportunistic human pathogens. Gram-negative
4.4 Enacyloxin IIa bacteria also display a striking variability in genome size (400 kb
4.5 Bromoalterochromides to >6 Mb) and genomic G + C content (25–80%) which is
4.6 Polycyclic tetramate macrolactams a testament to their inherent capability to adapt to such an
5. Ribosomally synthesized and post-translationally modi- extraordinary range of environmental conditions.
ed peptide natural products (RiPPs) To gain a selective advantage in their particular habitat and/or
5.1 Pantocin A microbial community, bacteria produce an assortment of speci-
5.2 Capistruin and microcin J25 alised metabolites with diverse biological activities.1 Well-known
6. Other examples include enzyme inhibitors, metal chelators, toxins,
6.1 Promysalin bioregulators, immunosuppressants, insecticides, surfactants
6.2 Tabtoxin and signalling molecules. However, the majority of known spe-
6.3 Carbapen-2-em-3-carboxylate (C3C) cialised metabolites produced by Gram-negative bacteria exhibit
antimicrobial activity (antibacterial, antifungal, antiprotozoal)2
Department of Chemistry, University of Warwick, Gibbet Hill Road, Coventry, UK. and these will be the focus of this review. Antimicrobial
E-mail: G.L.Challis@warwick.ac.uk compounds serve a multitude of ecological functions and
† These authors contributed equally. purposes, such as elimination of food competitors, weapons in
712 | Nat. Prod. Rep., 2017, 34, 712–783 This journal is © The Royal Society of Chemistry 2017
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Review Natural Product Reports
predation and protection of the host.3 Structurally, they range development of advanced genome sequencing technologies,
from simple molecules, such as benzaldehyde,4 to large and cultivation-independent techniques and meta-omic approaches
complicated metabolites with rare functional groups and unique has further revealed the untapped biosynthetic potential of many
heterocyclic ring systems, such as the ecteinascidins.5 previously-overlooked Gram-negative bacterial species, including
To date, the overwhelming majority of antimicrobial metab- those that are difficult to isolate from the environment.11–17
olites reported derive from Gram-positive Actinobacteria.2 While many biosynthetic pathways from Gram-negative
Natural products from these organisms, together with their bacteria supercially resemble those of well-studied Actino-
biosynthetic pathways, have therefore been the subject of bacteria, a more detailed examination reveals much novel
extensive study for many decades. In comparison, Gram-negative chemistry, as well as unprecedented biosynthetic mechanisms.
bacteria have received relatively little attention. In recent years, In this review, we present a comprehensive overview of the
however, they have become increasingly recognised as a rich and antimicrobial metabolites known to be produced by Gram-
underexplored source of novel antimicrobial compounds with negative bacteria (see Table 1 at the end of this article)18–657
therapeutic potential. Pseudomonas species appear to be the most and highlight a selection of metabolites with interesting and
prolic producers of such metabolites,6 together with marine and unusual biosynthetic pathways, in an effort to illustrate the
terrestrial myxobacteria7–9 and cyanobacteria,10 each of which are remarkable chemical diversity and biosynthetic ingenuity of
known to produce several hundreds of antibiotics.2 Apart from this diverse and underexplored group of bacteria.
these well-known producer organisms, Gram-negative bacteria
from other diverse phylogenetic classes have contributed to
antimicrobial metabolite discovery (Fig. 1). Recently, the 2. Polyketides
Polyketides from Gram-negative bacteria are a highly diverse
Joleen Masschelein was born in group of natural products that display a wide range of biological
1986 and attended KU Leuven properties. Many have been reported to possess antimicrobial
(Belgium), where she obtained activity (Fig. 2). Despite their structural diversity, these
a BSc, MSc and PhD in Bioscience compounds derive primarily from simple acyl and malonyl
Engineering under the guidance thioester building blocks. The biosynthetic logic for polyketide
of Prof Rob Lavigne. In 2015, she assembly is remarkably similar to that employed for fatty acid
joined the group of Prof Greg biosynthesis. However, there are key differences between poly-
Challis at the University of War- ketide synthases (PKSs) and fatty acid synthases (FASs).658,659
wick as a Marie-Sklodowska PKSs utilise a wider range of starter units and extender units. In
Curie postdoctoral research some systems the a-carbon of malonyl-CoA extender units can
fellow. Her research focuses on be methylated during chain assembly. The extent of b-carbon
diverse aspects of antimicrobial processing aer each round of chain elongation can also vary
metabolites from Gram-negative and several in cis modications to the growing chain, such as
bacteria, including biosynthetic pathway elucidation and engi- tetrahydropyran formation, double bond isomerisation and O-
neering, as well as molecular mode of action and resistance studies. methylation can occur. Moreover, other modications to the
Matthew Jenner obtained a BSc Greg Challis is the Monash

in Biochemistry from the Warwick Alliance Professor of
University of Nottingham in Sustainable Chemistry (Chem-
2010. He received his PhD in ical and Synthetic Biology),
Chemistry in 2014 under the a joint appointment between the
guidance of Prof Neil Oldham at Department of Chemistry and
the University of Nottingham, the Warwick Integrative
where he applied biological Synthetic Biology Centre at the
mass spectrometry to elucidate University of Warwick and the
the molecular mechanisms of Department of Biochemistry and
biosynthetic enzymes. He Molecular Biology at Monash
currently works as a post- University. He is also a member
doctoral research fellow with of the Warwick Antimicrobial
Prof Greg Challis at The University of Warwick, where he is Interdisciplinary Centre and an Associate Investigator of Monash's
pursuing a genomics-driven approach for the discovery of new ARC Centre of Excellence in Advanced Molecular Imaging. His
natural products and biosynthetic pathways in bacteria belonging research interests encompass the discovery, biosynthesis, bioengi-
to the Burkholderia genus. neering and mechanism of action of bioactive natural products. He
is a recipient of the Royal Society of Chemistry's 2017 Interdisci-
plinary Prize.
This journal is © The Royal Society of Chemistry 2017 Nat. Prod. Rep., 2017, 34, 712–783 | 713
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Fig. 1 Taxonomic overview of Gram-negative genera known to produce antimicrobial metabolites.
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Fig. 2 Examples of antimicrobial polyketides produced by Gram-negative bacteria.
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growing polyketide chain can be introduced by enzymes that act various Sorangium cellulosum strains.177,187,681 These compounds
in trans. interfere with fungal osmoregulation, by overstimulation of the
Three distinct classes of PKSs have been dened: types I, II and high-osmolarity glycerol (HOG) protein kinase signalling
III. Type I PKSs are large multifunctional proteins, whereas type II pathway. This leads to build-up of high intracellular levels of
systems consist of a set of discrete monofunctional proteins.17–660 glycerol which, in the absence of high external osmotic
Type III PKSs lack the acyl carrier protein (ACP) found in type I concentrations, ultimately results in rupture of the cell
and II systems, and typically use a single active site to catalyse membrane and cell death.682–684 Ambruticins have been shown
decarboxylative oligomerisation of malonyl-CoA thioesters and to cure mice of coccidioidomycosis and histoplasmosis with
subsequent cyclisation of the resulting poly-b-ketomethylene minimal adverse effects and are therefore excellent leads for
chain.661 Modular type I PKSs consist of repeated groups of cata- antifungal drug development.685
lytic domains termed a module. Each module typically catalyses Ambruticins and jerangolids have related trisubstituted
a single round of chain elongation and a series of a-/b-carbon tetra- and di-hydropyrans, respectively, appended with
modication reactions. The minimal set of domains required for branched unsaturated hydrocarbon chains of differing struc-
chain elongation in a module is an acyltransferase (AT) domain, ture. In jerangolid this chain terminates with a d-lactone,
which transfers a malonyl group from malonyl-CoA onto the 40 - whereas in ambruticin it contains a methylcyclopropane fol-
phosphopantetheine prosthetic group of the acyl carrier protein lowed by a second tetrahydropyran. Jerangolids A (1) and D (2)
(ACP) domain, and a ketosynthase (KS) domain, which receives differ by the presence of a hydroxyl group at C-18 in the latter
the growing polyketide chain from the ACP domain in the and variations to the ambruticin core structure occur at C-5,
upstream module and catalyses its condensation with the malonyl which has a hydroxyl group or a mono-, di-, or tri-methylated
group loaded by the AT domain. Optional ketoreductase (KR), amino group in the various known congeners (Fig. 3). Incor-
dehydratase (DH), enoyl reductase (ER) and C-methyltransferase poration of [2-13C]acetate into ambruticin results in coupling
(MT) domains modify the a- and b-carbons in the b-ketothioester between C-4 and C-5 in the 13C NMR spectrum.686 This suggests
resulting from chain elongation. A thioesterase (TE) domain, that the carboxyl carbon of a malonyl extender unit is excised
which catalyses release of the fully assembled polyketide chain during polyketide chain assembly (Fig. 3, see below).
from the PKS via macrolactonisation or hydrolysis, is oen Both ambruticin and jerangolid are assembled by cis-AT
appended to the C-terminus of the nal module, although several PKSs that, for the most part, follow canonical biosynthetic logic,
other chain terminating domains are also known.662,663 with some noteworthy exceptions. The sequence of reactions
The direct correlation oen observed between the module and catalysed by AmbA/JerA, AmbB/JerB, AmbC/JerC and AmbD/
domain organisation of a PKS and the structure of its product is JerD, in ambruticin and jerangolid biosynthesis, respectively,
referred to as co-linearity, and allows plausible biosynthetic appears to be identical, and gives rise to the common inter-
pathways to be proposed on the basis of sequence analyses.664,665 mediate 3 (Fig. 3). Recent in vitro experiments have provided
However, two phylogenetically-distinguishable classes of insight into the unusual catalytic activity of the DH domains in
modular type I PKSs, with distinct module architectures, have modules 3 and 4 of AmbC/JerC. Using simplied synthetic
been identied. In cis-AT PKSs an AT domain is present within substrate analogues, the DH domain in module 3 was shown to
each module, whereas in trans-AT systems the modules lack AT catalyse sequential dehydration and tetrahydropyran forma-
domains and a single standalone AT enzyme supplies malonyl- tion.687 Employing a similar approach, the DH domain in
CoA extender units to each of them.666–668 Although at rst module 4 was shown to catalyse a,b-dehydration, g-epimerisa-
glance the modular architecture of trans-AT PKSs resembles that tion, and a,b to b,g-double bond isomerisation; a set of trans-
of their cis-AT counterparts, the two systems have evolved inde- formations that is hypothesised to occur prior to methylation of
pendently.669,670 Indeed, closer inspection reveals that trans-AT the a-position by the trans-acting MT encoded by ambM/jerM
PKSs have several unusual features, such as non-elongating KS (Fig. 3).688
domains, peculiar domain orders and modules that are split The last common intermediate 3 in the jerangolid and
across two proteins.668,671–674 As a result, co-linearity rules are ambruticin biosynthetic pathways is proposed to undergo chain
difficult to apply to trans-AT systems and sequence-based elongation with a malonyl extender unit followed by a methyl-
predictions are more challenging. However, the substrate speci- malonyl extender unit catalysed by modules 6 and 7, respec-
city of KS domains can be inferred, unlike in cis-AT PKSs, tively, in JerE. Reduction of the b-keto group aer the rst round
providing an alternative means of predictive analysis.670,675–677 of chain elongation affords a hydroxyl group for release of the
Gram-negative bacteria harbour both cis-AT and trans-AT PKSs,678 polyketide chain via d-lactone formation by the C-terminal TE
and some of the more fascinating examples will be highlighted in domain of JerE. The resulting intermediate is elaborated to
this section. For additional information on polyketide biosyn- jerangolids A (1) and D (2) via a series of post-PKS tailoring
thesis and the many PKS architectural variants, we refer the reactions.689 In contrast, in the ambruticin pathway, common
reader to several comprehensive reviews.660,668,679,680 intermediate 3 is proposed to undergo chain elongation with
a methylmalonyl extender unit, keto reduction and dehydration
catalysed by module 6 of AmbE. Module 7 of AmbE then appears
2.1 Ambruticins and jerangolids to catalyse three successive rounds of chain elongation, keto
Ambruticins and jerangolids are structurally-related polyketides reduction and dehydration to generate a conjugated hexaene
that exhibit potent antifungal activity and are produced by (Fig. 3). Interestingly, module 8 in AmbF lacks an AT domain,
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Fig. 3 Comparison of the proposed biosynthetic pathways for ambruticins VS4 (8), VS3 (9) and VS1 (10), and jerangolids A (1) and D (2). Enzymes
and catalytic domains that catalyse unusual transformations are coloured in gold and are discussed in the text. Incorporation patterns for labelled
acetate, propionate and methionine into ambruticin VS-5 (11) are shown in the inset.
and with no stand-alone AT encoded within the ambruticin chain by the TE domain, generates ambruticin J (4), which is
biosynthetic gene cluster (BGC), this activity may be supplied by proposed to be epoxidised by the putative avin-dependent
module 7 or hijacked from fatty acid biosynthesis.456,686 The b- monooxygenase AmbJ. It has been postulated that the C-3
keto thioester formed by chain elongation with a malonyl hydroxyl group in the resulting intermediate opens the
extender unit by module 8 in AmbF is hypothesised to undergo epoxide via spontaneous nucleophilic attack at C-7 to form
a rearrangement triggered by protonation of the polyene. This ambruticin F (5).686 Either AmbN or AmbQ is then proposed to
results in formation of the characteristic tri-substituted cyclo- oxidise 5 to 5-ketoambruticin (6), which undergoes AmbR-
propane of ambruticin and a transient cyclopropanone, which catalysed transamination to give ambruticin VS5 (7). Disrup-
is proposed to be hydrolytically cleaved by the putative a/b- tion of ambS led to the accumulation of 7, consistent with the
hydrolase (H) domain in AmbF to form the corresponding b- notion that AmbS catalyses the N-methylation reactions
carboxy-thioester (Fig. 3). Oxidative decarboxylation of this required to produce ambruticins VS1 (8), VS3 (9) and VS4 (10).686
intermediate, catalysed by the putative avin-dependent mon- Ambruticin S (11) is proposed to arise from reduction of the
ooxygenase AmbI, would generate a b-hydroxy thioester. AmbI is keto group in 6 by either AmbN or AmbQ.
a homologue of PedG from the pederin BGC,667 which is
hypothesised to catalyse oxidative polyketide chain cleavage. 2.2 Gladiolin and etnangien
The roles of the putative pyridoxal-binding domain (Px) at
the C-terminus of AmbE and the A-PCP didomain encoded by Etnangien (12) is a macrolide antibiotic with potent activity
ambG are currently unknown. Further studies are required to against a range of Gram-positive bacteria, including Mycobac-
fully elucidate the mechanism of the fascinating polyketide terium smegmatis (MIC ¼ 1 mg ml1). It is produced by the
chain rearrangement in ambruticin biosynthesis. myxobacterium Sorangium cellulosum and mode-of-action
A nal round of chain elongation by module 9 in AmbF, studies revealed that it is an inhibitor of bacterial nucleic acid
followed by hydrolytic release of the fully assembled polyketide polymerases, in addition to the HIV-1 reverse transcriptase.690
However, it is highly unstable primarily due to the conjugated
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Fig. 4 Comparison of the structures of etnangien (12) and gladiolin (13), and the trans-AT PKSs responsible for their assembly. Structural
differences between etnangien and gladiolin are highlighted by the coloured boxes. The sole difference between the two PKSs is the
replacement of an ACP domain in EtnD with an ER domain in GbnD1. Enzymes and catalytic domains discussed in the text are highlighted in gold.
The ATs highlighted in green are predicted to be malonyl-CoA specific. AH ¼ acyl hydrolase.
acyclic hexaene in its C-21 side chain, which is sensitive to light, to modify the polyketide chain during its assembly. Interest-
molecular oxygen and acid. The methyl ester derivative of ingly, both clusters possess genes (etnB/gbnB) encoding stand-
etnangien is more stable, but less bioactive than the natural alone ATs for which the substrate specicity cannot be pre-
product.211 Total synthesis of the macrolide core of etnangien dicted. It has been proposed that these ATs may be responsible
showed that it is inactive, suggesting that the C-21 side chain for loading of the presumed succinyl starter unit onto the rst
plays a key role in target binding. Thus, etnangien has not been ACP of the PKS. Alternatively, the starter unit may be transferred
further developed due to the apparently essential nature of its directly onto the active site Cys residue of the module 1 KS
highly unstable C-21 side chain. domain from succinyl-CoA. This hypothesis is supported by
Recently, Challis and co-workers reported the discovery of phylogenetic analyses, which place this domain in clade VI,
gladiolin (13), a structurally-related metabolite produced by the alongside other KS domains that utilise similarly unusual
clinical isolate Burkholderia gladioli BCC0238 with low toxicity starter units.670
and promising activity against Mycobacterium tuberculosis The module and domain organisation of the etnangien and
(MIC ¼ 0.4 mg ml1 against the H37Rv strain and activity is gladiolin PKSs is remarkably similar. 70 of the 71 catalytic
observed against isoniazid and isoniazid/rifampicin-resistant domains in the two assembly lines appear to identical. The only
clinical isolates).448 The most striking structural difference difference is the substitution of an ACP domain in module 1 of
between etnangien and gladiolin is the C-21 side chain. The the etnangien PKS with an ER domain in the gladiolin PKS. The
highly labile hexaene in the former is replaced by a 2-methyl- b-keto thioester resulting from elongation of the succinyl starter
1,5,7-triene in the latter. As a consequence, gladiolin does not unit with a malonyl extender unit by the KS domain in module 1
suffer the acute stability problems of etnangien. In addition, the of EtnD/GbnD1 is proposed to be converted to the corre-
C-38/C-39 double bond in the etnangien side chain is replaced sponding b-methyl-a,b-unsaturated thioester by a hydrox-
by a single bond in gladiolin and the methyl group at C-6 of the ymethylglutaryl-CoA synthase (HCS) enzyme cassette.691 In the
etnangien macrolide core is replaced by a hydrogen atom gladiolin PKS, the carbon–carbon double bond in this inter-
(Fig. 4). mediate is proposed to be reduced by the ER domain in module
Complete genome sequences of S. cellulosum So ce56 and B. 1 of GbnD1. Module 1 of EtnD does not contain an ER domain.
gladioli BCC0238, coupled with targeted gene inactivation Thus, the corresponding b-methyl-a,b-unsaturated thioester
experiments, have facilitated the identication of the etnangien intermediate is not reduced in etnangien biosynthesis.
and gladiolin BGCs.211,448 Each cluster harbours six large genes The ER domain in GbnD1 may also be responsible for
encoding trans-AT PKS subunits, designated etnDEFGHI and reducing the a,b-unsaturated thioester intermediate resulting
gbnD1–D6, respectively. In both cases, the PKS genes are anked from chain elongation, ketoreduction and dehydration by
by a conserved set of genes encoding enzymes that are predicted module 5 of the gladiolin PKS.448 An analogous transformation
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does not occur in module 5 of the etnangien PKS.211 The synthetase (IleRS), thus blocking protein synthesis.20,697 Crystal
consequence appears to be that this module catalyses two structures of the S. aureus IleRS in complex with Ile-tRNA and
further rounds of chain elongation, ketoreduction and dehy- pseudomonic acid A (14) have been determined (Fig. 5).698,699
dration, before passing the polyketide chain onto module 6. The Strains of P. uorescens that produce the antibiotic are resistant to
nal carbon–carbon double bond of the hexaene in the C-21 it because they have a modied IleRS, with markedly reduced
side chain of etnangien is installed by the action of the afore- mupirocin affinity.700,701 Eukaryotic IleRSs also have a low affinity
mentioned HCS enzyme cassette on the module 6 chain elon- for mupirocin, thus permitting clinical use.700 The structurally-
gation intermediate. related antibiotics thiomarinols A–G (18–23), consisting of a pseu-
Both the gladiolin and etnangien PKSs harbour C-MT domonic acid-like moiety conjugated to holothin, are produced by
domains in modules 14 and 16, which is congruent with the Pseudoalteromonas species (Fig. 5).529–531,702
presence of methyl groups at C-4 and C-8 of gladiolin, but Extensive genetic and biochemical studies have established
not at C-4, C-6 and C-8 of etnangien. Presumably, the C-MT many key aspects of mupirocin biosynthesis. These are well-
domain in either module 14 or module 16 of etnangien summarised in other reviews,533,668,703 and will not be covered in
PKS is able to methylate the module 15 chain elongation detail here, where we restrict the discussion to an overview of the
intermediate, although further experiments are needed to verify current model for mupirocin and thiomarinol assembly. An
this hypothesis.211 unusual trans-AT PKS assembles the monic acid component
common to both antibiotic complexes (Fig. 6). MmpD/TmpD
appear to lack a loading module and the KS domain of module
2.3 Mupirocin and the thiomarinols
1 is proposed to accept the acetyl starter unit directly from acetyl-
Mupirocin is a polyketide antibiotic complex originally isolated CoA. The structure of the intermediate hypothesised to be
from Pseudomonas uorescens.692 The pseudomonic acids A (14), B attached to the C-terminal ACP domain of MmpD/TmpD is in
(15), C (16) and D (17) components of the complex are used topi- accord with the catalytic domains in modules 1–4, except that an
cally to treat infections caused by Gram-positive bacteria. These ER domain appears to be missing from module 3. This catalytic
include impetigo, furuncle and conditions caused by methicillin- activity is proposed to be supplied in trans by the ER domain of
resistant Staphylococcus aureus (MRSA).693–696 Mupirocin competi- MmpC/TmpC. MupA/TmlA is believed to catalyse hydroxylation at
tively inhibits the adenylation of isoleucine by isoleucyl-tRNA
Fig. 5 (A) Structures of pseudomonic acids (14–17), thiomarinols (18–23) and holothins (24–29). (B) Crystal structure of the S. aureus isoleucyl-
tRNA synthetase in complex with Ile-tRNA (black) and pseudomonic acid (teal spheres). Functional and structural domains are highlighted and
labelled. The figure was generated by overlaying PDB files 1FFY and 1JZS.
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Fig. 6 Overview of the current model for mupirocin biosynthesis (top) and comparison with the pathway proposed for assembly of the
structurally-related thiomarinols (bottom).
C-4 of the intermediate bound to C-terminal ACP domain of with the product of the mmpD/mmpA assembly line and the
MmpD/TmpD,668 although the timing of this transformation has mmpE, mupA, mupT and mupW trans-acting tailoring enzymes.
yet to be experimentally veried. The non-elongating KS0 domain Hydrolytic release of the resulting ester affords pseudomonic
located at the N-terminus of MmpA/TmpA may act as a gatekeeper acid B (15). MupU and MupO are together proposed to load 15
to ensure that the chain is not further elongated prior to hydrox- onto the standalone ACP MacpE, whereupon the monic acid
ylation.672,676,677 A trans-acting HCS cassette converts the b-keto- moiety is subjected to additional tailoring reactions catalysed by
thioester resulting from chain elongation by module 6 into the MupV, MupC and MupF.708 Hydrolytic release of the product
corresponding b-methyl-a,b-unsaturated thioester.691,704 At this yields pseudomonic acid A (14) (Fig. 6).
point, various shunt products can arise in the mupirocin pathway The holothin moiety of the thiomarinols belongs to a class
which are described in detail elsewhere.705,706 The epoxidase (Epx) of structurally-related antibiotics known as the dithiolo-
domain of MmpE is proposed to oxidise the di-substituted double pyrrolones, which possess a broad spectrum of activity and
bond in the intermediate bound to module 6 of MmpA to an are produced by Gram-positive, as well as Gram-negative,
epoxide. Gene knock-out experiments have implicated MupW and bacteria (Fig. 5).532,620,709 Holomycin is believed to inhibit
MupT in the formation and hydroxylation, respectively, of the bacterial transcription, a somewhat different target to that of
mupirocin tetrahydropyran. A homologue of mupT is absent from the thiomarinols (see above). The thiomarinol BGC is located on
the thiomarinol BGC, accounting for the absence of the C-8 a plasmid in Pseudoalteromonas sp. SANK 73390 and consists of
hydroxyl group in the monic acid moiety of the thiomarinols. two sub-clusters. The rst is highly homologous to the mupir-
Interestingly, mupirocins W6 (30) and W1 (31), which appear to ocin BGC, reecting the structural similarity between the mar-
result from nucleophilic attack of the C-7 hydroxyl group on the inolic acid portion of the thiomarinols and the pseudomonic
epoxide, accumulate in a mupW mutant. This provides insight into acids (Fig. 5). The second contains a set of genes (holA-G) that
the probable timing of the epoxidation reaction.707 are homologues of the genes within the holomycin BGCs of
MmpB appears to be an iterative PKS that is responsible for Streptomyces clavuligerus and Yersinia ruckeri.620,710,711 In vitro
assembly of a 9-hydroxynonanoyl thioester, which is condensed analysis of each enzyme encoded by the S. clavuligerus cluster
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Fig. 7 Proposed biosynthetic pathway for the elansolids. The DH domain believed to be involved in dehydration at C-23, triggering the intramolecular
Diels–Alder reaction, is coloured in gold. Incorporation patterns into elansolid A (33) of labelled acetate and methionine are shown in the inset.
has elucidated the pathway for dithiolopyrrolone biosyn- (35) in the nature of their C-25 substituent and are very likely
thesis,711 allowing a plausible pathway for assembly of holothin isolation artefacts.
and its coupling to marinolic acid to be proposed (Fig. 6). In an independent study, the els gene cluster encoding
a cryptic trans-AT PKS in Chitinophaga pinensis was shown to
direct the biosynthesis of elansolids B1 (35) and D2 (34).713
2.4 Elansolids Subsequently, a highly similar gene cluster (the ela cluster) was
The elansolids (32–38) are an unusual group of polyketides with identied in the C. sancti genome, allowing a plausible
antimicrobial and cytotoxic activity, originally isolated from the biosynthetic pathway for the elansolids to be proposed
gliding bacterium Chitinophaga sancti, formerly known as (Fig. 7).714 Feeding studies with isotope-labelled precursors
Flexibacter sp.712 Elansolids A (33), B1 (35), B2 (36) and B3 (37), conrmed that elansolid A (33) is a polyketide and that the PKS
which possess a common bicyclo[4.3.0]nonene core were iso- starter unit is para-hydroxybenzoic acid (Fig. 7).714 The elansolid
lated from extracts of C. sancti.712 Elansolid A (33) exists as two PKS exhibits many of the features commonly found in other
atropisomers, one of which exhibits pronounced activity against trans-AT PKSs, such as HCS cassette-mediated b-branching,
Gram-positive bacteria and mouse broblast cells compared to non-elongating ketosynthase domains, and a trans-acting ER
the other.712 Elansolid B1 (35) is the seco-acid of elansolid A (33), domain, which is hypothesised to reduce an a,b-unsaturated
whereas elansolids B2 (36) and B3 (37) differ from elansolid B1 thioester intermediate generated by module 3.
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Elansolid A3 (32) was subsequently also identied as such as a-hydroxy/keto acids and carboxylic acids into their
a metabolite of C. sancti.715 This compound possesses a para- products.718,719 Consequently, NRPSs are capable of generating
quinone methide in place of the para-hydroxybenzyl alcohol remarkable structural diversity and complexity using only
group in elansolid B1 (35), and provides important insights into a limited catalytic repertoire.
the likely mechanisms underlying elansolid biosynthesis.714 An NRPS chain extension module contains three core
Thus, it was proposed that loss of the hydroxyl group from C-23 domains: an adenylation (A) domain, a condensation (C)
of the a,b-unsaturated thioester intermediate generated by domain and a peptidyl carrier protein (PCP). The A domain
module 9 of the PKS (possibly catalysed by one of the two DH selects an amino acid building block from the cellular pool,
domains in this module) would generate the para-quinone activates its carboxyl group by adenylation and tethers it to
methide, triggering formation of the characteristic bicyclo the downstream PCP domain via a thioester linkage.720 A 40 -
[4.3.0]nonene core of the elansolids via an intramolecular phosphopantetheinyl (40 -PP) prosthetic arm attached to the
Diels–Alder cycloaddition.714,715 Model studies employing PCP is responsible for formation of the thioester linkage via
synthetic analogues of the proposed para-quinone methide nucleophilic attack of its thiol group on the aminoacyl ade-
precursor provided experimental support for this hypothesis. nylate intermediate. C domains catalyse peptide bond
Subsequent trapping of the para-quinone methide with the formation between the aminoacyl thioester bound to the PCP
carboxyl group in elansolid A3 (32) gives elansolid A (33), domain within the same module and the peptidyl (or ami-
whereas intermolecular addition of water, methanol or noacyl) thioester intermediate attached to the PCP domain of
ammonia to the para-quinone methide affords elansolids B1 the preceding module. The resulting peptidyl thioester
(35), B2 (36) and B3 (37), respectively. intermediate then undergoes the next round of chain elon-
Elansolid D2 (34) is proposed to originate from elansolid B3 gation catalyzed by the C domain within the downstream
(35) via protonation-triggered loss of the C-9 hydroxyl group module.721,722 The specicity of A domains can be predicted by
followed by intramolecular trapping of the resulting hepta- analyzing a set of 8–10 residues in the active site that are
trienyl cation to form a tetrahydrofuran.713 Similarly, elansolid hypothesised to play an important role in substrate recogni-
D1 (38), a minor constituent of the extracts, appears to derive tion.723,724 In addition to the core C, A and PCP domains, NRPS
from elansolid A3 (32) via a Grob-like fragmentation, which re- modules can contain one or more auxiliary domains that
aromatises the para-quinone methide and creates a heptatrienyl modify the aminoacyl or peptidyl thioester intermediates.
cation that is trapped by addition of the C-7 hydroxyl group.715 These transformations oen introduce structural changes or
additional functional groups that are essential for biological
3. Nonribosomal peptides activity and/or increase the stability and structural complexity
of the product. Such domains include epimerisation (E) and
Nonribosomal peptides (NRPs) represent a second major class C/N-methyltransferase (MT), which are responsible for
of specialized metabolites produced by Gram-negative bacteria inverting a-carbon stereochemistry and installing a-carbon or
(Fig. 8, Table 1).2 They form a large family of structurally N-methyl groups, respectively. In some modules, hetero-
complex and diverse natural products that oen exhibit potent cyclisation (Cy) domains are found in place of C domains.
antimicrobial activity and/or other industrially-important These catalyse elongation of the peptide chain with serinyl,
properties, such as insecticidal, cholesterol-lowering, threoninyl or cysteinyl thioesters, followed by cyclo-
immuno-suppressant and anti-cancer activities.716 Given their dehydration to form oxazolines or thiazolines, which can be
enormous commercial value, there is a continuous interest in further oxidized to oxazoles or thiazoles by avin-dependent
discovering new biologically active NRPs. oxidation (Ox) domains.716,725–727 In trans reduction of the
Large enzymatic assembly lines, known as nonribosomal thiazolines formed by Cy domains to the corresponding
peptide synthetases (NRPSs) are responsible for the biosyn- thiazolidines by standalone reductases is also known.728
thesis of NRPs.716,717 These modular multi-enzymes use Chain initiation modules in NRPSs typically lack a C domain,
similar enzymatic logic to type I modular PKSs. Each NRPS except those involved in lipopeptide biosynthesis, which use
module consists of a set of core catalytic domains that are such a domain to catalyze N-acylation of the chain initiating
responsible for the selection, activation and incorporation amino acyl-PCP intermediate.716 Several mechanisms are
of a single amino acid building block into the growing chain. known for release of the fully-assembled peptide chain from
In addition, optional catalytic domains are sometimes the PCP domain in the nal NRPS module. Macrocyclization
present. These modify the incorporated amino acid in or hydrolysis is typically catalysed by a C-terminal thio-
several different ways, for example by N-methylating it, or esterase (TE) domain, whereas a similarly situated thioester
epimerizing the a-carbon atom. The order, substrate speci- reductase (TR) catalyzes chain release via reductive cleavage
city and number of NRPS modules usually correlates with of the C–S bond.729 C domains are also known to catalyse
the size and sequence of the peptide assembled. This chain release, typically via intra- or intermolecular amide or
colinearity principle enables bioinformatics-guided struc- ester bond formation.730–732 For further information on the
ture predictions. structural biology and enzymology of NRPSs, the interested
In addition to the 21 standard proteinogenic a-amino acids, reader is referred to several excellent reviews dedicated to
NRPSs are also able to incorporate a wide range of non- these topics.716–718,726,733,734
proteinogenic amino acids, as well as other building blocks
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Fig. 8 Examples of nonribosomal peptides with antimicrobial activity isolated from Gram-negative bacteria.
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3.1 Teixobactin lipid II and lipid III, respectively.649,736 Resistance to teixobactin

has yet to be detected and seems unlikely to emerge quickly,
Traditionally, antibiotic discovery has been conducted by
given that it binds to multiple highly conserved extracellular
screening laboratory-grown cultures of microorganisms for
targets, none of which are proteins.
activity against other microorganisms. However, the over-
Teixobactin is biosynthesised by an NRPS (Txo1–2) that
whelming majority of microbial species in nature remain

largely follows textbook assembly line logic, catalyzing the
uncultivated under laboratory conditions and are difficult to
sequential incorporation of 11 amino acids, followed by chain
isolate via conventional cultivation techniques. To gain access
to the vast untapped reservoir of bioactive natural products release via intramolecular cyclization (Fig. 9).736 However, a few
produced by such microorganisms, several new cultivation intriguing aspects of teixobactin assembly merit more detailed
discussion.
technologies have been developed, for example the isolation
Firstly, two non-proteinogenic amino acids, N-methyl-D-
chip or iChip.735 This diffusion chamber enables the in situ
phenyl-alanine (N-Me-Phe) and L-allo-enduricididine (L-End),
cultivation of microorganisms by providing contact with the
are incorporated into teixobactin. The N-Me-Phe residue is
natural environment through semi-permeable membranes. One
derived from N-methylation of the phenylalaninyl PCP-thioester
such cultured organism, a new species of b-proteobacteria
intermediate attached to module 1 by the MT domain. L-End is
named Eleheria terrae, was found to produce a novel dep-
sipeptide antibiotic, called teixobactin (39).736 Teixobactin has an unusual non-proteinogenic amino acid found in only two
potent activity against multidrug-resistant Gram-positive path- other nonribosomal peptide antibiotics: enduricidin and man-
nopeptimycin.737,738 Interestingly, both compounds, like teix-
ogens and shows no toxicity against mammalian cells. It
obactin, bind the peptidoglycan precursor lipid II, albeit in
synergistically inhibits peptidoglycan and cell wall teichoic acid
distinct regions.739 While little is known about the formation of
biosynthesis by binding to the pyrophosphate-sugar moiety of
Fig. 9 (A) Proposed biosynthetic pathway for teixobactin (39). NRPS domains discussed in the text are highlighted in gold. (B) Pathway for
enduricididine biosynthesis in mannopeptimycin producer S. hygroscopicus NRRL 30439.
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L-End in E. terrae, its biosynthesis in mannopeptimycin- hydroxy-myristoyl-CoA with a serinyl thioester attached to the
producing Actinobacteria has been the subject of considerable PCP domain within the loading module. The resulting N-acyl-
investigation.739,740 L-End biosynthesis starts from L-Arg and serinyl thioester is elongated with a prolinyl thioester,
involves three enzymes encoded by genes within the man- yielding an N-acyl dipeptidyl thioester tethered to the second
nopeptimycin BGC: MppP, MppQ and MppR (Fig. 9).739–741 A PCP domain of BraB. Elimination of water from the serine
homologous trio of enzymes, EndPQR, is encoded by the residue converts it to dehydroalanine. It is currently unclear
enduricidin BGC.742 MppP is a PLP-dependent L-Arg a-deami- whether the condensation domain in module 1 of the NRPS or
nase/g-hydroxylase that uses molecular oxygen to convert L-Arg BraC is responsible for this reaction.32,746 Chain release of the
to 2-oxo-4-hydroxy-5-guanidinovaleric acid,739 which undergoes lipo-dipeptide is catalysed by a phylogenetically-distinct TE
MppR-catalysed dehydration and subsequent cyclization to domain that mediates nucleophilic addition of the dehy-
form an iminoimidazoline.740 Reductive amination of the droalanine b-carbon atom on the thioester carbonyl carbon to
resulting a-keto acid, catalyzed by the PLP-dependent amino- give a 5,6-bicyclic tetrahedral intermediate, which collapses via
transferase MppQ, generates L-End.739 elimination of the active site Ser hydroxyl group to yield the
Another interesting feature of the teixobactin NRPS is the product.32 This unusual ring closure mechanism is promoted by
presence of bifunctional condensation/epimerization (C/E) the nitrogen lone pair of the enamine, which stabilises the
domains in modules 1, 4, 5 and 8. C/E domains are incipient cation formed at the dehydroalanine a-carbon during
commonly found in NRPSs responsible for the assembly of the reaction. The resulting imminium ion is deprotonated to
cyclic lipopeptides in Pseudomonas sp. and epimerise the a-
stereocenter of the upstream aminoacyl/peptidyl thioester prior
to condensation.6,743 This unusual subclass of C domains can be
identied by the presence of an elongated active site motif
(HHI/LxxxxGD).743 In the teixobactin assembly line, C/E
domains account for the incorporation of four D-congured
amino acids: N-Me-D-Phe, D-Gln, D-Ile and D-Thr.
Finally, the C-terminus of Txo2 harbours two TE domains.
Tandem C-terminal TE domains are also present in the lyso-
bactin, syringopeptin, arthrofactin and massetolide NRPSs in
Lysobacter and Pseudomonas sp., respectively.6,744 In vitro studies
with the lysobactin synthetase have revealed that the rst TE
domain mediates cyclization and product release. The second
TE domain is believed to be released from the NRPS by
proteolytic cleavage, allowing it to function as a type II TE that
deacylates misprimed PCP domains.744 In the arthrofactin
synthetase, both TE domains appear to work cooperatively to
effect chain release via macrocyclization. The second TE
domain is proposed to have been recruited during the course of
evolution to improve macrocyclization efficiency.745
3.2 Brabantamide A
Brabantamide A (SB-253514) contains an unusual 5,5-fused
bicyclic ring system conjugated to a rhamnosylated 3-hydroxy
myristoyl moiety (40, Fig. 10). It was rst discovered by
SmithKline Beecham Pharmaceuticals in culture extracts
of Pseudomonas uorescens as a nanomolar inhibitor of
lipoprotein-associated phospholipase A2 (Lp-PLA2), an attrac-
tive target for the treatment of artherosclerosis,27,28 and was also
found to exhibit signicant activity against Gram-positive
bacteria and specic fungi and oomycetes.29,30 The 12.8 kb
brabantamide BGC is present in the genomes of several Pseu-
domonas species and is comprised of ve genes, designated
braABCDE.32,746 The core biosynthetic genes are braA (or lpiA),
braB (or lpiB) and braC (or lpiC), which encode a rhamnosyl
transferase, a bimodular NRPS and a avin-dependent Baeyer–
Villiger monooxygenase, respectively. Fig. 10 Proposed biosynthetic pathway for brabantamide A (40) from
In the rst step of brabantamide A biosynthesis, the N- P. fluorescens. The unusual C–C bond-forming TE domain is high-
terminal C domain of BraB catalyses the condensation of 3- lighted in gold.
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reform an enamine that undergoes racemisation at the proline tyrosine derivative 3-hydroxy-5-methyl-O-methyltyrosine (3-OH-
a-carbon, followed by a Baeyer–Villiger oxidation catalysed by 5-Me-OMe-Tyr) by an unusual NRPS (EtuA1–3) (Fig. 11).755 ET-
BraC, which appears to be highly selective for the R-epimer of 743 biosynthesis is proposed to be initiated by the acyl-CoA
the enamine. Flavin-dependent monooxygenases that catalyse ligase (AL) domain of EtuA3, which is hypothesised to catalyse
similar ring expansion reactions are involved in the biosyn- the activation of a cryptic long-chain fatty acid, most likely
thesis of mithramycin and urdamycin in Streptomyces argilla- myristic acid, as an acyl adenylate and subsequent transfer of
ceus and S. fradiae, respectively.747–749 The resulting 5,7-bicyclic the acyl group onto the downstream ACP domain. Although no
intermediate (SB-315021) is co-produced alongside brabanta- acylated ET-743-related metabolites have yet been isolated, in
mide A in minor quantities.28 Conversion of the 5,7 ring system vitro biochemical studies have revealed that an analogous acyl
of SB-315021 to the 5,5 ring system of brabantamide A is the chain is a crucial substrate recognition element for several of
result of a allylic 1,3-transposition. the enzymes in the related saframycin A biosynthetic
The hydroxyl group of the N-acyl moiety undergoes BraA- pathway.761 The acyl thioester generated by the loading module
catalysed rhamnosylation, although the precise timing of the of EtuA3 is predicted to be condensed with a cysteinyl thioester
reaction is unclear.746 Genes involved in rhamnose biosynthesis attached to the PCP domain in module 1 of EtuA3. The resulting
are absent from the brabantamide BGC. As is typically the case N-acylcysteinyl thioester 41 is proposed to undergo elongation
for other rhamnosylated metabolites, these are likely located with an unusual glycolyl thioester by EtuA1. The ET-743 gene
elsewhere in the genome.32,746 The brabantamide biosynthetic cluster encodes homologs (EtuP1–P2, EtuF9) of the trans-
machinery in Pseudomonas sp. C52 assembles two minor ketolase–ACP complex that has been shown to generate the
congeners of 40, which differ in the nature of the N-acyl moiety. glycolyl thioester extender unit incorporated during the
Brabantamide B contains a 3-hydroxy palmitoleic acid-derived biosynthesis of NDM and QNC. This complex catalyses the
acyl chain and has similar antibacterial activity to 40, whereas transfer of a glycolyl unit from a pentulose-5-phosphate onto
brabantamide C has a 3-hydroxy palmitoyl group and shows a dedicated ACP.762 In vitro analysis has revealed that the acyl-
a twofold increase in potency.746 ated depsipeptide thioester 42 resulting from EtuA1-catalysed
elongation of 41 with the glycolyl thioester is reductively
released as an aldehyde 43 from the PCP domain of EtuA1 by the
3.3 Ecteinascidin-743 TR domain of EtuA2.755 Koketsu and co-workers were the rst to
Marine and terrestrial invertebrates, such as beetles, insects, demonstrate that the corresponding TR domain in the safra-
sponges, dinoagellates and tunicates, are a prolic source of mycin NRPS (SfmC-TR) is able to catalyse such a reaction.761
natural products with potential medical applications. However, Furthermore, they were able to show, through extensive in vitro
ever-accumulating evidence points to bacterial symbionts as the investigations, that the resulting aldehyde is condensed with
true producers of many of the bioactive metabolites isolated the amino group of a 3-OH-5-Me-OMe-Tyr thioester attached to
from such organism.667,750–752 The majority of these symbionts the SfmC PCP domain to form an imine, which undergoes
have yet to be cultivated outside of their natural host and have a Pictet–Spengler reaction catalysed by the C domain of SfmC.
therefore long been refractory to functional analysis. Recently, On the basis of sequence similarity, the C domain in EtuA2 is
the advent of cultivation-independent methods and meta-omic predicted to catalyse an analogous transformation. These
approaches has provided access to the genomes of invertebrate- unusual C domains have been referred to as a “Pictet–Spen-
derived microbial consortia and has enabled a fuller exploration glerase” domains and contain a signature HxxxxD motif in place
of their biosynthetic capabilities.753,754 of the conserved HHxxxDG motif found in canonical C
One such study has led to the identication of the BGC for domains.761
the antitumor drug ecteinascidin-743 (ET-743, Yondelis, Tra- The 3-OH-5-Me-OMe-Tyr unit is believed to be bio-
bectedin, 53) in the genome of an uncultivated tunicate synthesised from Tyr via a dedicated pathway that involves
symbiont.650,755 ET-743 is a tetrahydro-isoquinoline with potent hydroxylation, C-methylation and O-methylation, catalysed by
antibacterial and anticancer activity that was originally isolated EtuH, EtuM2 and EtuM1, respectively.755 The homologous
from extracts of the tunicate Ecteinascidia turbinata. Recently, enzymes involved in the biosynthesis of this non-proteinogenic
a g-proteobacterial endosymbiont, designated Candidatus amino acid in the saframycin A and safracin pathways have
Endoecteinascidia frumentensis, was identied as the true been extensively studied in vitro, and by gene deletion and
producer of this compound.650,755 The pentacyclic core of ET-743 heterologous expression experiments.763,764
is also found in several antimicrobial and antitumor The intermediate resulting from condensation of aldehyde
compounds from terrestrial bacteria, including saframycin MX1 43 with the 3-OH-5-Me-OMe-Tyr thioester, is proposed to
from M. xanthus,756 safracin B (Fig. 8) from P. uorescens,757 and undergo reductive release to generate aldehyde 44, again cata-
saframycin A,758 naphthyridinomycin (NDM)759 and quinocarcin lysed by the TR domain of EtuA2.755 According to the model
(QNC)760 from Streptomyces species. The biosynthetic pathways proposed by Koketsu and coworkers, aldehyde 44 is then
for these terrestrial tetrahydroisoquinolines have been exten- condensed with a second EtuA2-bound 3-OH-5-Me-OMe-Tyr
sively investigated, greatly facilitating the development of thioester to form a bis-tetrahydroquinoline.761 The TR domain
plausible models for ET-743 biosynthesis. then catalyses a third round of thioester reduction to afford
The main framework of ET-743 is assembled from a cysteine aldehyde 45, which likely undergoes spontaneous ring closure
residue, a hydroxyethyl moiety and two molecules of the to form hemiaminal 46.755 Thus, construction of the pentacyclic
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Fig. 11 Proposed biosynthetic pathway for ET-743 (53) in Candidatus Endoecteinascidia frumentensis. The unusual Pictet–Spengler-mediating
C domain is highlighted in gold.
core of ET-743 involves iterative use of single TR and C domains yet unidentied enzyme catalyses formation of the thioether to
to catalyse thioester reduction and Pictet–Spengler cyclisation, generate the known biosynthetic intermediate ET-583 (49).755
respectively, of several distinct substrates. The ability of the Subsequent N-methylation of the secondary amine catalysed by
Eta2 TR domain to accept substrates from different ACP EtuM4 would yield ET-597 (50).650 Another as yet unidentied
domains is remarkable and is reminiscent of the function of the enzyme is presumed to be responsible for the oxidative deam-
TE domain from the pikromycin synthase.765 ination of ET-597 to yield ET-596 (51). The methylene dioxy-
EtuF3, which shows sequence similarity to penicillin acy- bridge in ET-594 (52) is proposed to be installed by one of the
lases, is proposed to be responsible for cleavage of the cryptic N- FAD-dependent monooxygenase enzymes EtuO1/2/3/4. Finally,
acyl group to form pre-ET-743 (47). A similar maturation process condensation of ET-594 with a further 3-OH-5-Me-OMe-Tyr
has been observed in the late stages of pyoverdin assembly in P. thioester, followed by another Pictet–Spengler reaction and
aeruginosa.766 One of the aromatic rings in 47 is proposed to reductive release of the resulting intermediate from EtuA2,
undergo hydroxylation and subsequent acetylation to yield would yield ET-743 (53).5,650,755
intermediate 48. These reactions are believed to be catalysed by The potent anticancer activity of ET-743 originates from its
a putative FAD-dependent monooxygenase (EtuO1/2/3/4) and carbinolamine moiety which can be converted into an electro-
acetyltransferase (EtuY), respectively.650,755 EtuO1/2/3/4 are philic iminium ion that alkylates the DNA minor groove. ET-743
similar in sequence to SfmO2, which is proposed to install is clinically approved in Europe for the treatment of advanced
a hydroxyl group on the pentacyclic core of saframycin.767 An as so-tissue sarcoma and relapsed ovarian cancer. Currently, it is
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made in a lengthy semi-synthetic manufacturing process from respectively.94,777 In vitro biochemical experiments have estab-
fermentation-derived safracin B.5 Identication of the full lished that the malonyl-CoA-ACP transacylase from the primary
complement of biosynthetic genes might pave the way for metabolic FAS functions as the AT in this process.779 A similar
economical and large-scale production of ET743 via a heterolo- case of functional crosstalk between FAS and PKS systems has
gous expression approach. been described for the biosynthesis of FK228 in the b-proteo-
bacterium Chromobacterium violaceum.780

In the next step, the trienoyl thioester is condensed with the
4. Hybrid polyketide-nonribosomal amino group of a (3S)-b-Phe thioester attached to AdmI. (3S)-b-
peptide natural products Phe is biosynthesised from L-Phe by the phenylalanine amino-
mutase AdmH, which utilises an autogenous 4-methylidene-
Due to the architectural, organizational and functional simi-
imidazol-5-one cofactor for catalysis.777 In-depth investigation
larities between type I modular PKSs and NRPSs they have
of the mechanism and stereochemistry of the AdmH-catalysed
evolved the ability to communicate with each other and mix
reaction revealed that the amino and pro-(3S) hydrogen atom
modules to form hybrid assembly lines.716,768 During transfer of
are eliminated from L-Phe and are interchanged with inversion
the growing chain across NRPS/PKS interfaces KS and C
of conguration at both reacting centres, resulting in exclusive
domains serve as chain elongation catalysts by accepting
production of (3S)-b-Phe.781 The stand-alone A domain AdmJ
upstream PCP-bound peptidyl thioesters and ACP-bound poly-
activates the carboxyl group of (3S)-b-Phe and specically selects
ketide thioesters, respectively, thereby switching efficiently
the free-standing carrier protein AdmI for aminoacyl thioester
between C–C bond and C–N bond formation. Examples of
formation. Thus, protein–protein interactions appear to play
antimicrobial hybrid polyketide–peptide metabolites produced
a key role in ensure the correct product results from this
by Gram-negative bacteria include the myxalamid electron
dissociated assembly line.782
transport inhibitors,769 the antistaphylococcal metabolite kali-
The formation of the amide bond between the octatrienoyl
mantacin/batumin,99 the DNA gyrase inhibitor albicidin,636
thioester and the AdmI-tethered (3S)-b-Phe thioester is cata-
and the antifungal/antitumor agent epothilone A (Fig. 12,
lysed by the unusual transglutaminase (TG) homologue
Table 1).770
AdmF.777 Prior to the condensation reaction, an active site Cys
residue in AdmF, within a conserved Cys–His–Asp catalytic
4.1 Andrimid triad, accepts the octatrienoyl chain from AdmA. Hence, AdmF
Andrimid (54) is a potent, broad-spectrum antibiotic with an combines characteristics of both C domains (amide bond
unconventional target, i.e. the b-subunit of bacterial acetyl-CoA formation) and KS domains (involvement of an acyl-enzyme
carboxylase (ACC).97,771–773 Since ACC catalyses the rst intermediate), and exemplies a novel type of condensation
committed step in bacterial fatty acid biosynthesis by convert- catalyst in PKS/NRPS assembly lines. In vitro biochemical
ing acetyl-CoA to malonyl-CoA, its inhibition leads to imme- studies with puried recombinant AdmF have demonstrated
diate cell growth arrest. Due to its high selectivity for bacterial that the enzyme has a broad substrate tolerance and is able to
over eukaryotic ACCs, andrimid represents a promising candi- accept a range of other AdmA-tethered substrates, such as cro-
date for further development as an antibacterial drug.771 tonyl, butyryl, octanoyl, hexanoyl and phenylacetyl thioesters.782
Both andrimid and its congener moiramide B (55) have been Furthermore, AdmF can utilize an N-acetylcysteamine (NAC)
isolated from a wide variety of g-proteobacteria, including thioester of octatrienoic as an acyl donor in vivo. This opens up
Pseudomonas uorescens, Vibrio coralliilyticus, Pantoea agglom- the possibility of producing novel andrimid derivatives via
erans and Enterobacter cloacae, as well as several Serratia a mutasynthesis approach, involving feeding of analogues of
species.93,96,97,774–776 The biosynthesis of these pyrrolidinedione- the octatrieonyl NAC thioester to mutants of P. agglomerans
containing natural products involves a highly dissociated defective in octatrienoyl-AdmA biosynthesis.782
hybrid PKS/NRPS assembly line, with each carrier protein The octatrienoyl-b-Phe thioester resulting from the action of
located on a separate subunit (Fig. 13). Interesting features of AdmF is linked via an amide bond to a valine thioester bound to
this unusual pathway include: polyunsaturated fatty acid the PCP domain of AdmK. This reaction is believed to be cata-
(PUFA) biosynthesis by a type II PKS, catalysis of peptide bond lysed by a second TG-like enzyme, AdmS.777 The remaining PKS/
formation by transglutaminase-like enzymes, incorporation of NRPS enzymes AdmO, AdmP and AdmM further elongate the
the unusual amino acid (S)-b-phenylalanine, AT-less PKS resulting AdmK-bound octatrienoyl-dipeptidyl thioester with
modules and post-assembly line formation of the pyrrolidine- a glycinyl unit and two malonyl-CoA-derived acetyl units. The C-
dione.94,777 Heterologous expression of the andrimid BGC terminal TE domain of AdmM is then proposed to catalyse
(admA-T) from P. agglomerans Eh335 in E. coli has facilitated hydrolysis of the resulting b-ketothioester to yield a linear b-
detailed dissection and engineering of the andrimid biosyn- keto acid.94 Subsequent intramolecular aldol condensation,
thetic pathway.94,778 followed by decarboxylation, dehydration, reduction of the
Andrimid biosynthesis starts with assembly of an AdmA- exomethylene group to a methyl group and oxidation of the
tethered octatrienoyl thioester (hexadienoyl thioester in the adjacent methylene carbon to a keto group would yield andri-
case of moiramide B) by the iterative type II PKS enzymes AdmC, mid (54). AdmL, AdmN and AdmB are proposed to be involved
AdmD and AdmE, which encode homologues of a KR, a KS- in this series of transformations. Structure–activity relationship
chain length factor (CLF) didomain, and a DH, studies with andrimid and chemically-synthesized analogues
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Fig. 12 Examples of hybrid polyketide-nonribosomal peptide natural products with antimicrobial activity from Gram-negative bacteria.
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Fig. 13 Proposed biosynthetic pathway for andrimid (54) and moiramide B (55). The unusual transglutaminases (TG) that catalyse peptide bond
formation are highlighted in gold.
have revealed that the pyrrolidinedione moiety of andrimid bacteria provide nutrients to support nematode growth and
is essential for antibacterial activity. In contrast, structural development by degrading the insect biomass. When nutrient
variation of the octatrienoyl chain is better tolerated and levels drop, the nematodes are recolonized by the bacteria
could be exploited to optimize the pharmacological prole of before re-emerging in the soil to search for new insect prey.786,787
andrimid.783 Among the various kinds of antibacterial and antifungal
Several efforts have also been made to generate andrimid metabolites that are produced by Xenorhabdus species, the
derivatives via engineering of the valine-specic A domain of xenocoumacins are the most abundant.793 Xenocoumacin-1 (61)
AdmK. Liu and coworkers constructed a chimeric andrimid displays potent broad spectrum antibacterial and antifungal
assembly line by swapping the A domain of AdmK with activity and has also been shown to have antiulcer activity.483
a promiscuous A domain from the cytotrienin hybrid NRPS– The xenocoumacin BGC in X. nematophila comprises 14 genes
PKS. The activity of the resulting catalytically-impaired NRPS (xcnA–N) that encode a hybrid modular PKS–NRPS assembly
was restored via directed evolution to generate a mutant capable line, as well as enzymes involved in self-resistance, precursor
of producing an andrimid derivative containing 2-amino- biosynthesis, export and maturation.794 To avoid self-toxicity,
butyrate instead of Val.778 Later, Kelleher and coworkers the xenocoumacin biosynthetic machinery assembles biologi-
employed a directed evolution approach to directly target the cally inactive prodrugs, named pre-xenocoumacins A–E (56–60)
active site of the AdmK A domain and modify its substrate that are cleaved and activated upon secretion (Fig. 14).483 The
specicity. Using saturation mutagenesis and a structure-based biosynthesis of the prexenocoumacins is proposed to be initi-
screening assay they obtained four P. agglomerans mutants ated by N-capping of the PCP-bound Asn thioester starter unit
capable of producing andrimid derivatives containing Ile, Leu, with one of ve different acyl chains, catalysed by the N-
Ala or Phe in place of the Val residue.784 terminal C domain of XcnA. Following epimerisation of the a-
carbon in the Asn residue and condensation of the resulting N-
acyl-D-asparaginyl thioetser with an arginyl thioester, module 2
4.2 Xenocoumacin of the assembly line is proposed to utilise (2R)-hydroxymalonyl-
The xenocoumacins are dihydroisocoumarins produced by CoA to extend the chain with a glycolyl unit. The xenocoumacin
several strains of Xenorhabdus nematophila.482,785 Bacteria of the BGC encodes four proteins (XcnBCDE) with a high degree of
genus Xenorhabdus are well known for their mutualistic sequence similarity to a set of enzymes responsible for the
symbiotic relationship with soil-dwelling Steinernema nema- assembly of hydroxymalonyl-ACP from 1,3-bisphosphoglycerate
todes.786,787 They live in a specialized region of the nematode gut in the biosynthesis of zwittermicin A, an antibiotic produced by
and, along with their host, they form an entomopathogenic various Bacillus sp.795
complex that can infect and kill a wide range of insect larvae. Another interesting feature of the xenocoumacin assembly
Upon invasion of a suitable insect prey, the bacteria are released line is the lack of an AT domain in module 5. Presumably, the
in the circulatory system of the insect where they secrete an ACP domain in this module is loaded with a malonyl extender
assortment of bioactive specialised metabolites that participate unit either by the AT domain from an adjacent module or by an
in suppressing the insect immune system, killing the insect AT encoded elsewhere in the genome. Alternatively, the
host and protecting the insect cadaver from various pro- and malonyl-CoA-ACP transacylase from the FAS complex could
eukaryotic food competitors.788–792 At the same time, the provide the missing AT activity in trans, as has been observed in
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Fig. 14 Proposed biosynthetic pathway for xenocoumacin-1 (61) and xenocoumacin-2 (62). Catalytic domains discussed in detail in the text are
highlighted in gold.
the biosynthesis of andrimid (see Section 4.1) and FK228.779,780 Upon secretion, the biologically inactive prexenocoumacins
Chain release via lactonisation, followed by (presumably spon- are activated by XcnG, a bifunctional protein with an N-terminal
taneous) intramolecular aldol condensation and aromatisation periplasmic peptidase domain and a C-terminal transmembrane
yields the pre-xenocoumacins. Interestingly, the nal module of domain that specically removes the N-acyl-D-Asn unit to
the assembly line lacks a C-terminal TE domain, which is form the xenocoumacin-1.483 Analogous reactions involving
commonly utilised for chain release via lactonisation in poly- membrane-bound and D-Asn-specic peptidases occur in the
ketide biosynthesis. It is currently unclear which enzyme is biosynthesis of zwittermicin, colibactin and amicoumacin.793
responsible for chain release in xenocoumacin biosynthesis. Furthermore, genes encoding homologs of the loading module
in the xenocoumacin assembly line and XcnG have also been
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found in several other BGCs from various bacterial genera, sug- mechanism.803 Noticeable differences between the Zmn and Pfa
gesting that cleavage of acylated D-Asn residues constitutes enzymes are the number of ACP and DH domains and the
a widespread mechanism for the activation of natural product presence of a PLP-dependent aminotransferase (AMT) domain
“prodrugs”. XcnG is believed to rely on the action of an ABC in Zmn12. The zeamine II assembly line lacks a PfaB homologue
transporter and the outer membrane protein TolC for the but contains additional stand-alone KR (Zmn13) and TR
excretion of xenocoumacin-1.483 In the insect, the antibiotic kills (Zmn14) enzymes. The biosynthesis of zeamine II is proposed to
gut microbes as well as a wide range of bacterial and fungal food be initiated by an acetyl-CoA starter unit and likely proceeds via
competitors. Analysis of the global transcriptional response of B. repeated cycles of chain elongation, ketoreduction, dehydration
subtilis to xenocoumacin-1 suggests that the antibiotic has and enoyl reduction. In selected cycles, the b-keto group is
a similar mode of action to protein synthesis inhibitors and reductively aminated by the AMT domain in Zmn12, rather than
might target arginyl-tRNA synthetase.796 Xenocoumacin-1 is also being reductively removed.572,802 Analogous PLP-dependent
toxic to X. nematophila, which employs a resistance mechanism AMT domains are found within the mycosubtilin and micro-
that detoxies any xenocoumacin-1 that is taken back up. This cystin biosynthetic assembly lines in B. subtilis and several
involves the fatty acid desaturase XcnN and the saccharopine cyanobacterial genera, respectively.804,805 Aer the last round of
dehydrogenase XcnM which together catalyse redox reactions chain extension, the b-keto group is believed to undergo
that result in cleavage of the guanidino group and the formation reduction to an alcohol rather than conversion to an amine,
of a pyrrolidine to form xenocoumacin-2 (62) (Fig. 14).794,797 This affording a tetraamino-hydroxyalkyl thioester attached to the
metabolite has reduced antibacterial activity and is no longer ACP domain of Zmn10. The precise factors that govern
able to inhibit the growth of fungi.797 Intriguingly, a related programming and chain length control in this highly unusual
resistance mechanism was found in the amicoumacin-producing iterative assembly line are still unclear. Zmn14 has been shown
strain Xenorhabdus bovienii.798 Amicoumacins (Fig. 12) are to function as an NADH-dependent thioester reductase and is
structurally related to the xenocoumacins but lack the guanidino proposed to catalyze the reductive release of the fully-assembled
functional group. As a result, the amino group of the Asn starter chain. The resulting aldehyde then undergoes reductive ami-
unit is not incorporated into a pyrrolidine, but instead undergoes nation to yield zeamine II (63).572
N-acetylation. The resulting N-acetyl-amicoumacin derivatives In a parallel pathway, the NRPS subunits Zmn16 and Zmn17
are biologically inactive. Molecular modelling studies have catalyse the sequential condensation of Asp (via its b-carboxyl
shown that N-acetylation critically interferes with the ability of group), His, Asn, Asn, Thr, Val and to form a hexapeptidyl
amicoumacin to bind to the E-site of the ribosome and inhibit thioester. This undergoes one or two rounds of elongation with
ribosomal translocation.798 malonyl-CoA-derived acetyl units and subsequent reduction of
the resulting b-keto group(s) catalysed by the PKS Zmn18 to
generate hexapeptide–monoketide and hexapeptide–diketide
4.3 Zeamines thioesters, respectively. Condensation of these thioesters with
The zeamines are an unusual class of polyamine-containing the primary amino group of zeamine II (63), catalyzed by the
hybrid polyketide-nonribosomal peptide metabolites produced standalone C domain Zmn19, produces prezeamine (64) and
by Serratia plymuthica RVH1.572,799 Apart from being toxic to prezeamine I (65).572,806 At some point during the assembly of
a wide range of pro- and eukaryotic organisms such as bacteria, these compounds, the amido group of the D-Asn residue
fungi, oomycetes, plants and nematodes, some zeamines also displaces the hydroxyl group of the Thr residue, affording
possess anti-proliferative activity against human tumor a macrolactam. The precise timing of this reaction is unknown,
cells.570,572,573,800,801 This broad spectrum antagonistic activity is as is the enzyme responsible for it. Finally, the prezeamines are
linked to the cationic amphiphilic nature of the zeamines and partially converted into zeamine (66) and zeamine I (67) by the
their ability to directly interact with and disrupt the integrity of action of Zmn22, an acylpeptide hydrolase that specically
cellular membranes.573 The zeamine antibiotic complex is cleaves off the N-terminal pentapeptide in a post-assembly
a mixture of ve structurally related compounds: prezeamine, processing step.572
zeamine, prezeamine I, zeamine I and zeamine II, all of which The prezeamines are exported from the cell along with zea-
contain a 40-carbon penta-amino-hydroxy-alkyl chain conjugated mine, zeamine I and zeamine II as part of an antibiotic complex.
via an amide bond to a variable peptide–polyketide moiety.572,799 Minimal inhibitory concentrations (MIC) assays with suscep-
Zeamine (66) and zeamine II (63) were rst isolated from the tible E. coli and S. aureus strains have demonstrated that the
phytopathogen Dickeya zeae by Zhang and co-workers.800,802 prezeamines are more effective at inhibiting growth than zea-
The zeamines are assembled in a convergent process by two mine II but have fourfold reduced activity compared to zeamine
separate assembly lines: an iterative type I PKS homologous to and zeamine I.572 Presumably, the action of Zmn22 represents
polyunsaturated fatty acid (PUFA) synthases (Zmn10–14) and a strategy of S. plymuthica RVH1 to expand the structural and
a hybrid NRPS/PKS (Zmn16–19).572 The Zmn10–13 complex functional diversity of the zeamine complex. The prezeamine
catalyses assembly of the polyamino alcohol zeamine II proteolytic processing mechanism thus deviates from the
(Fig. 15). Zmn10, Zmn11 and Zmn12 have a high degree of “prodrug” activation mechanism involved in the biosynthesis of
sequence similarity to PfaA, PfaC and PfaD, respectively, which xenocoumacin, amicoumacin, zwittermycin and colibactin.793 It
assemble long-chain PUFA's such as eicosapentaenoic acid is unclear whether the macrocyclic peptide resulting from pre-
(EPA) and docosahexaenoic acid (DHA) via an interactive zeamine cleavage is also bioactive.
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Fig. 15 (A) Proposed pathway for the biosynthesis of the zeamine complex from S. plymuthica RVH1. The unusual AMT and KR components of
the PUFA-like PKS are highlighted in gold. (B) Chemical structures of the fabclavines (68–77), nemaucin (78) and cabanillasin (79).
Recently, several metabolites that show a close structural from S. plymuthica and D. zeae.574,788,807,808 One remarkable
resemblance to the prezeamines were identied from two difference though is the lack of a zmn22 homologue. Conse-
different entomopathogenic Xenorhabdus strains.788 The fab- quently, the fabclavines do not undergo a proteolytic processing
clavines (68–77) are produced as a mixture of closely-related step and only full-length metabolites are produced. It is
congeners with minor differences in the length of the poly- tempting to speculate that proteolytic processing of the fab-
amino and polyketide moieties, and in the amino acid compo- clavines may have become undesirable in relation to the bio-
sition of the hexapeptide (Fig. 15). The fabclavine BGCs in both logical function(s) of these metabolites and that the zmn22
Xenorhabdus strains are highly similar to the zeamine BGCs homologue may therefore have been lost due to selective
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pressure. This hypothesis is supported by the fact that the a Burkholderia gladioli strain during cocultivation with the
proteolytic cleavage site has been eliminated in several of the fungus Rhizopus microsporus.456,810,812
fabclavine congeners by incorporation of a proline residue in Enacyloxin IIa selectively inhibits bacterial protein synthesis
place of the valine residue. by binding to ribosomal elongation factor (EF)–Tu.813 EFs play
The prezeamines and fabclavines also bear a remarkable an important role in protein synthesis by delivering aminoacyl-
structural resemblance to nemaucin (78), an antimicrobial tRNAs to the ribosome in a GTP-dependent manner. Enacyloxin
metabolite from an entomopathogenic Xenorhabdus cabanillasii acts by locking the elongation factor in its GTP-bound confor-
strain (Fig. 15).494 Intriguingly, in nemaucin the peptide–poly- mation. This prevents the release of the EF–Tu–GDP complex
ketide moiety is connected to a polyagmatine chain instead of from the tRNA, causing the ribosome to stall. The X-ray crystal
a polyamine chain, and the N-terminal Asp residue is connected structure of the E. coli EF–Tu in complex with enacyloxin IIa and
to the adjacent His residue via its a-carboxyl group. The same the non-hydrolysable GTP analogue guanylyliminodiphosphate
Xenorhabdus cabanillasii strain has also been shown to produce has revealed the structural basis for this mode of action
the zeamine II-equivalent of nemaucin, termed cabanillasin (Fig. 16).457 Enacyloxin binds to the same site in EF–Tu as kir-
(79) (Fig. 15).493 The gene cluster that directs the production of romycin, a structurally unrelated but functionally similar anti-
these highly unusual metabolites has not yet been identied, biotic from Streptomyces collinus.457
nor is anything known about the biosynthesis of the poly- The enacyloxin BGC has been identied in the genome of B.
agmatine moiety. ambifaria AMMD and a pathway for its biosynthesis has been
proposed, involving construction of a 27-carbon thioester by
a large type I modular PKS. The (1S,3R,4S)-3,4-dihydrox-
ycyclohexane carboxylic acid (DHCCA) with which the thioester
4.4 Enacyloxin IIa
is condensed is believed to derive from shikimate.456 The
Enacyloxin IIa (82) is an unusual polyene antibiotic with activity enacyloxin biosynthetic assembly line has several distinctive
against Gram-positive and Gram-negative bacteria.809–811 It is features, including an unusual PKS chain initiation process,
particularly active against multidrug-resistant Burkholderia and an unusual mechanism for chain release, involving inter-
multivorans (MIC ¼ 6.5 mg ml1), Burkholderia dolosa (MIC ¼ 7.5 molecular esterication proposed to be catalysed by an NRPS-
mg ml1) and Acinetobacter baumannii (MIC ¼ 2 mg ml1) strains, like C domain (Fig. 17).
all of which are troublesome pathogens in healthcare Enacyloxin chain initiation is mediated by an atypical PKS
settings.456 It was rst isolated from the soil-dwelling Frateuria loading module within Bamb_5925, consisting of three catalytic
strain W-315 and has since then also been identied as domains: an N-terminal MT domain, a GCN5-related N-acetyl-
a metabolite of Burkholderia ambifaria AMMD and transferase (GNAT)-like domain and an ACP domain. GNAT
domains have been shown to catalyse decarboxylation of
malonyl-CoA and subsequent transfer of the resulting acetyl
group from CoA to the adjacent ACP domain.814 The presence of
a MT domain in a loading module is not very common and has
only been observed in two other biosynthetic pathways: those for
gephyronic acid and saxitoxin in the myxobacterium Cystobacter
violaceus and the cyanobacterium Cylindrospermopsis raciborskii,
respectively.815,816 Incorporation experiments with 13C-labelled
methionine have established that the MT domain in the
loading module of the gephyronic acid synthase utilizes S-
adenosyl-methionine as the methyl donor. In this myxobacterial
PKS, loading of the ACP domain with malonyl-CoA by the GNAT
domain is proposed to precede SAM-dependent methylation and
decarboxylation.816 However, direct biochemical evidence for this
is currently lacking. In the biosynthesis of enacyloxin, the loading
module is proposed to generate a propionyl starter unit, tethered
to the rst ACP domain within Bamb_5925.456
Bamb_5925-5919 form an unusual hybrid modular PKS that
contains several proteins with sequence similarity to cis-AT PKSs
(Bamb_5925-5920), as well as a single protein that is similar to
trans-AT PKSs (Bamb_5919).456 The only other biosynthetic
pathway reported to date that incorporates these two
phylogenetically-distinct protein classes into a single assembly
line is the kirromycin PKS.817 Surprisingly, modules 2–5 and 7–9
Fig. 16 X-ray crystal structure of the E. coli EF–Tu, bound to a non-
lack AT domains, despite having signicant homology to cis-AT
hydrolysable GTP analogue (top) and enacyloxin (middle right). PKSs. Given that no stand-alone AT-like enzymes are encoded by
Rendered from PDB entry 2KVN. genes within the enacyloxin gene cluster, the ACP domains within
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Fig. 17 Proposed pathway for enacyloxin IIa (82) biosynthesis in B. ambifaria AMMD. PKS/NRPS domains/proteins discussed in detail in the text
are highlighted in gold.
the AT-less modules are presumably loaded with a malonyl condensation with DHCCA, catalysed by the NRPS-like C domain
extender unit either by the AT domain(s) within module 1 and/or Bamb_5915, to form pre-enacyloxin (80).456 DHCCA is proposed
module 6, or by an AT encoded elsewhere in the genome.456 to be biosynthesized from shikimate through the action of four
Alternatively, the malonyl-CoA-ACP transacylase from primary enzymes: Bamb_5912, Bamb_5914, Bamb_5916 and Bamb_5918.
metabolism could provide the AT activity in trans, as is the case in The E-congured C-4/C-5 double bond in enacyloxin IIa is prone
the biosynthesis of andrimid (see Section 4.3) and FK228.779,780 to light-induced isomerization, generating a mixture of stereo-
A few discrepancies also exist between the bioinformatically isomers with different D-4,5 geometries.456
predicted structure of some intermediates in the pathway, and Pre-enacyloxin (80) is proposed to be converted to enacyloxin IVa
the nal structure of enacyloxin IIa. For example, module 6 (81) through a series of tailoring reactions, including regioselective
lacks the DH domain required to introduce the double bond chlorination of the polyene at C-11 by a avin-dependent chlorinase
between C-10 and C-11. Similarly, module 9 lacks the KR (Bamb_5928), stereospecic chlorination at C-18 by an a-ketoglu-
domain required to reduce the b-keto group to a hydroxyl group, tarate and non-heme iron-dependent chlorinase (Bamb_5931),
which then gets eliminated by the DH domain to form the carbamoylation by a carbamoyl transferase (Bamb_5930) and
penultimate double bond of the polyene. In both cases, the hydroxylation by an a-ketoglutarate and non-heme iron-dependent
corresponding domain within the downstream module, i.e. the hydroxylase (Bamb_5927). The possibility that some or all of these
DH domain within module 7 and the KR domain within module tailoring reactions take place during instead of aer PKS assembly
10, is believed to provide the missing activity in trans.456 has yet to be excluded.456 Interestingly, the chlorine atoms in
Unlike most other modular PKSs, the last module of the enacyloxins can be replaced by bromine atoms by replacing KCl in
enacyloxin PKS contains a KS0 domain in place of the usual TE the culture medium with KBr.818
domain. The KS0 domain is believed to transfer the fully- Enacyloxin IVa (81) is a known intermediate in enacyloxin
assembled polyketide chain from the ACP domain of module biosynthesis in Frateuria sp. W-315 and its conversion to enacy-
10 to the PCP domain within Bamb_5917. The polyketide chain is loxin IIa (82) has been shown to be catalysed by an extracellular
proposed to be released from Bamb_5917 via intermolecular pyrroloquinoline quinone (PQQ)-dependent oxidase.819 In B.
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organobromine compounds and have an impressive enzymatic

toolbox at hand, capable not only of adding multiple bromine
atoms to a single substrate but also of regioselective debromi-
nation.539,824–826 The bromoalterochromides occur as a mixture
of structurally related metabolites with variations in the amino
acid composition of the cyclic peptide, the length of the

aromatic polyene and the degree of bromination (Fig. 18).827
Apart from cytotoxic effects on developing eggs of sea urchins,
they exhibit antibacterial activity against B. subtilis.523,827 Fluo-
rescence microscopy studies of susceptible B. subtilis cells
treated with dibromoalterochromide have suggested a similar
mechanism of action to nisin, which disrupts the integrity of
cytoplasmic membranes.524
The 34kb bromoalterochromide BGC has been identied in
the genome of P. piscicida JCM20779 through MS/MS-guided
genome mining.524 Subsequent heterologous expression in E.
coli and targeted gene inactivation experiments have provided
insight into the biosynthetic pathway of these metabolites,
which involves type II FAS enzymes, three NRPS subunits and
a avin-dependent halogenase (Fig. 18).524,827 The assembly of
the aromatic polyene is initiated by conversion of L-tyrosine to
trans-p-coumaric acid, catalysed by the tyrosine ammonia lyase
AltA. The coumaric acid residue is then loaded onto the
standalone ACP AltB, before undergoing three (‘A’ metabolites;
83, 85, 87) or four (‘B’ metabolites; 84, 86, 88) rounds of 2-
carbon elongation, ketoreduction and dehydration, catalysed by
the type II fatty acid biosynthetic enzymes AltD, AltH and AltG.
The resulting polyunsaturated acyl thioester is condensed with
a threoninyl thioester attached to the PCP domain of AltK by its
N-terminal C domain. The E domain in AltK catalyses epime-
rization of the a-stereocenter of the resulting aminoacyl thio-
ester, and AltL and AltM further elongate the growing chain
with D-Val, L-Asn, D-Asn and D-Ile. Finally, the fully-assembled
Fig. 18 Proposed biosynthetic pathway for the ((di)bromo)alter- acyl-pentapeptide thioester is released from the last PCP
ochromides from marine Pseudoalteromonas sp. Substitution of the domain of AltM by macrolactonisation, catalysed by the C-
red Ile residue for Leu or Val yields ((di)bromo)alterochromides A0 /B0
terminal TE domain of AltM. At some point during the
and A00 /B00 , respectively.
assembly process, the avin-dependent halogenase AltN, in
conjunction with an as yet unidentied avin reductase,
brominates the aromatic ring, yielding the bromoalter-
ambifaria, the putative PQQ-dependent enzyme Bamb_5932 is ochromides (85, 86) and dibromoalterochromides (87, 88).
proposed to catalyze this transformation.456 Notably, the nal module of AltM can also incorporate D-Leu
and D-Val. The resulting metabolites are referred to as ((di)
bromo)alterochromides A0 /B0 and A00 /B00 , respectively.524,827
4.5 Bromoalterochromides
Members of the genus Pseudoalteromonas are marine g-pro-
teobacteria commonly found in seawater, sediments and in 4.6 Polycyclic tetramate macrolactams
association with marine invertebrates.820 In recent years, they Lysobacter is a genus of ubiquitous environmental bacteria,
have emerged as a rich source of chemically diverse natural known for their gliding motility, high genomic G + C content
products with important biological properties, including anti- (65–70%) and predatory behaviour.828 Like myxobacteria, Lyso-
bacterial, antifungal, antifouling and algicidal activities.15,821,822 bacter species are social predators, hunting their prey in groups
Among the antimicrobial metabolites produced by Pseu- and feeding on other pro- and eukaryotic micro-organisms.829
doalteromonas species, the bromoalterochromides attract Their broad spectrum of antagonistic activity has been attrib-
attention because of their unusual chemical structures, in uted to the production of a wide range of extracellular enzymes
particular their brominated aromatic polyenes (Fig. 18).523,823 and bioactive specialised metabolites.13,830 Several Lysobacter
Bromination is a common feature in marine natural products natural products have attracted considerable interest because of
due to the increased natural abundance of bromine in seawater. their potent antifungal activity, such as alteramide A (86),831
Marine Pseudoaltermonads are prolic producers of heat stable antifungal factor (HSAF, 92),427 lysobacteramide B
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(94)831 and xanthobaccin A,439 all of which belong to the poly- Stenotrophomonas (e.g. maltophilin) and Alteromonas (e.g.
cyclic tetramate macrolactam (PTM) family of hybrid non- alteramide A).832–837
ribosomal peptide–polyketide metabolites. Structurally, PTMs Over the past few years, detailed genetic, biochemical, struc-
feature a macrolactam that contains a tetramate and is fused to tural and mechanistic studies on different PTMs have provided
a set of two to three, ve- or six-membered carbocycles. Varia- considerable insight into their biosynthesis.428,429,835,837–841 All PTMs
tions exist in the size of the macrolactam (17- or 21-membered) have a common biosynthetic origin and the gene clusters that
and the oxidation state of individual carbon atoms. The direct their biosynthesis are highly conserved.837 The HSAF BGC in
remarkable structural diversity of PTMs is reected in the broad the biocontrol strain L. enzymogenes C3 has six genes encoding
variety of biological activities they possess, which ranges from a hybrid PKS/NRPS, a PTM hydroxylase, a set of three NADP/FAD-
antibacterial, antifungal, antiviral, antiprotozoal, antiulcer and dependent redox enzymes (OX1–OX3), and an alcohol dehydro-
antioxidant to cytotoxic.832 Apart from Lysobacter species, PTM's genase (OX4).427 Recently, four HSAF congeners, i.e. alteramide A
have been isolated from a variety of phylogenetically-diverse (95), 3-deoxy-HSAF (93) and lysobacteramides A (96) and B (94),
organisms, including marine sponges (e.g. geodin A), Strepto- were isolated from the same L. enzymogenes strain and their
myces sp. (e.g. frontalamides, dihydromaltophilin, ikar- absolute congurations were assigned by comparison of
ugamycin, pactamides) and other y-proteobacteria such as measured and calculated electronic CD spectra.831 The new
Fig. 19 Proposed biosynthetic pathway for the polycyclic tetramate macrolactams from L. enzymogenes C3. The unusual iterative PKS is
highlighted in gold.
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insights generated by these structural data have allowed a detailed section above on nonribosomal peptides, the production of
biosynthetic pathway for these metabolites to be proposed. The complex peptide-based molecules is directed by large, multi-
common precursor of these metabolites is assembled by an modular NRPS enzymes. A crucial feature of NRPSs is their
unusual iterative PKS–NRPS. The PKS assembles dodeca- ability to incorporate non-proteinogenic amino acids into the
pentaenoyl and b-hydroxy-dodecapentaenoyl thioesters that are core structures, increasing the structural diversity from the
condensed by the NRPS C domain with the d- and a-amino groups, proteinogenic paradigm.719 Although RiPPs are ribosomally
respectively, of an L-ornithinyl thioester bound to the NRPS PCP synthesised from the 20 common proteinogenic a-amino acids,
domain (Fig. 19).429 The C-terminal TE domain of the NRPS additional structural diversity is accessed through a wide variety
releases the resulting intermediate from the assembly line via of post-translational modications (PMs).846,847 Based on their
a Dieckmann-type cyclization to create a tetramate.429,842 structural features and types of biosynthetic pathway, RiPPs
The product 89 of the iterative PKS–NRPS undergoes a reduc- have recently been categorised into subfamilies.848 However,
tive cyclization cascade to generate the tricyclic system found in despite these differences, an underlying biosynthetic theme
HSAF, its 3-deoxy congener and lysobacteramide B. The cyclisa- exists for their production.
tion reactions that form the two 5-membered carbocycles are The ribosomally-biosynthesised precursor peptide usually
proposed to be catalysed by two of the three oxidoreductase consists of an N-terminal leader peptide and a C-terminal
enzymes OX1–3.831 OX1–3 are similar in sequence to the IkaB and ‘core’ which, following multiple PMs, results in the nal
PtmB12 enzymes, which have been shown to be responsible for product. The gene encoding the precursor peptide is usually
similar reactions in the biosynthesis of ikarugamycin and the situated in close proximity to those encoding the biosynthetic
pactamides, respectively.835,840,841 The third cyclization, which machinery required to conduct the PMs. During biosynthesis,
yields the six-membered carbocycle, is catalysed by OX4.840 By these enzymes recognise the N-terminal leader peptide
analogy with the proposed catalytic mechanisms of IkaC and allowing installation of specic PMs in the core region.849,850
PtmC,835,840 OX4 is proposed to catalyse the addition of the pro-R Recent studies have also shown the importance of the C-
hydride of NAD(P)H to the C-21/C-22 double bond. This triggers terminal region for this recognition process.604 Ultimately,
C–C bond formation between C-22 and C-11 and the resulting the leader peptide is proteolytically removed, a process that
vinologous enolate undergoes protonation at C-10 to generate can be accompanied by cyclisation of the polypeptide chain,851
a Z-congured C-2/C-3 double bond.831 to produce the mature product. In this section, several inter-
Finally, hydroxylation reactions at C-3 and C-20, proposed to esting examples of antibiotic RiPPs will be discussed.
be catalysed by the PTM hydroxylase and one of the OX1–3 However, for more detailed accounts and perspectives on RiPP
enzymes respectively, yield HSAF (92).831,838 Compared with biosynthesis we direct the reader to several recent
HSAF, lysobacteramide B (94) carries an additional methyl reviews.845,852–854
group on the nitrogen atom of the ornithine residue, which is
installed by an as yet unidentied methyltransferase.831 The C-3
hydroxyl group has been shown to be important for the anti- 5.1 Pantocin A
fungal activity of HSAF; 3-deoxy-HSAF (93) displays only weak Pantocin A (97) is a ribosomally-synthesised tripeptide rst
inhibitory activity against fungi.838 Interestingly, the PTM isolated from Pantoea agglomerans by Clardy and co-
hydroxylase, which is similar in sequence to sterol desaturases, workers.855,856 The non-pathogenic P. agglomerans is oen
shows considerable substrate promiscuity and can be used to accompanied in the wild by the epiphytic bacterium Erwinia
functionalise non-cognate PTMs.839 Alteramide A (95) and amylovora, which causes re blight disease in rosaceous
lysobacteramide A (96), which feature two fused ve-membered plants. Initial structural characterisation of 97 was
rings in their bicyclic system, are proposed to be shunt hampered by low yields and by the acid, base and thermal
metabolites.831 Overall, the PTM biosynthetic pathways illus- instability of the compound. However, using heterologous
trate the remarkable level of structural complexity that bacteria expression of a genomic-DNA cosmid library in E. coli,
can generate using only a limited palette of enzymes. sufficient quantities of 102 could be produced for structure
elucidation. In addition, this approach led to identication
of the BGC, indicating that pantocin is a RiPP-derived
5. Ribosomally synthesized and post- natural product.855,856
translationally modified peptide natural Pantocin A (97) exhibits potent antibiotic activity against E.
products (RiPPs) amylovora (IC50: 200 nM) via inhibition of L-histidinol phos-
phate aminotransferase, an enzyme that catalyses the conver-
RiPPs constitute an extensive group of natural products with sion of imidazole acetol phosphate to L-histidinol phosphate.855
vast structural diversity, ranging from small molecules to Interestingly, P. agglomerans produces another antimicrobial
proteins (Fig. 20). Although they possess a broad range of bio- agent active against E. amylovora, known as pantocin B
logical activities, antimicrobial and antifungal RiPPs are (Fig. 20), which inhibits N-acetylornithine transaminase.606,857
commonly produced by Gram-negative bacteria (see Table 1). Although structurally unrelated, both pantocin A and B act in
The wealth of bioactivities exhibited by RiPPs and recent a functionally similar manner; that is inhibition of
advances in the understanding of their biosynthesis have transaminase-catalysed steps in amino acid biosynthesis,
stimulated increased interest in these metabolites.843–845 In the where pantocin A inhibits histidine biosynthesis and pantocin
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Fig. 20 Examples of antimicrobial RIPPs produced by Gram-negative bacteria.
B, arginine biosynthesis. This observation is congruent with (Fig. 21, Route II). Both routes yield the bicyclic core, upon
the fact that both compounds are produced to suppress the which an oxidative decarboxylation can occur, catalysed by
growth of bacterial competitors in nitrogen-poor either PaaA or PaaB, yielding the pantocin precursor anked by
environments.855 leader and follower peptides.604
From a biosynthetic perspective, 97 originates from a Glu– As part of a PaaA characterisation study by Bowers and co-
Glu–Asn motif within the 30-residue precursor peptide, PaaP workers, N- and C-terminal truncations of PaaP were
(Fig. 21). Three additional genes are associated with the cluster; produced to examine the effect of the leader and follower
PaaA and PaaB are involved in post-translational tailoring of peptides upon PaaA activity. Interestingly, although the leader
PaaP, and PaaC is an efflux pump required for self-resistance.856 sequence, Met1–Thr15, was found to be absolutely required for
Following the biosynthesis of PaaP, the PaaA enzyme catalyses PaaA catalysis, removal of the follower still allows the rst
a double cyclisation–condensation and decarboxylation on condensation (either Route I or II) to occur.604 These observa-
PaaP, which could proceed via one of two routes. One possibility tions elegantly demonstrate the different inuence each region
is condensation of the backbone amide with the Glu16 residue, imposes upon PaaA-catalysed tailoring of RiPP precursors. In
followed by a Claisen-like condensation between the two Glu addition, the PaaA crystal structure solved in the same study,
residues, with the enolate nucleophile provided by Glu17 revealed the presence of a RiPP-Recognition Element (RRE)
(Fig. 21, Route I). Alternatively, the Claisen-like condensation (Fig. 21), which is believed to interact with PaaP and feed the
between Glu16 and Glu17 could precede backbone condensation pre-propeptide into the active site of PaaA.604,858 This partially
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Fig. 21 (A) Pantocin (97) biosynthetic gene cluster and proposed biosynthetic pathway. The two possible routes for backbone condensation and
Claisen-like condensation are highlighted in red and blue. (B) Crystal structure of the post-translational tailoring enzyme, PaaA. Individual
monomers are coloured gold and blue, and the RiPP-Recognition Element (RRE) is highlighted in red. Structure was rendered from PDB: 5FF5.
disordered region was shown to be stabilised upon interaction other Gram-negative organisms. The structure of 98 contains an
with PaaP, as peptide binding protects the RRE from eight-residue macrolactam, formed via an isopeptide linkage
proteolysis.604 between Gly1 and Glu8, through which the C-terminal tail is
threaded. The presence of bulky aromatic residues (Phe19 and
Tyr20) on the top and bottom face of the ring act as steric ‘plugs’,
5.2 Capistruin and microcin J25 securing the tail within the ring (Fig. 22).860,861 Currently, MccJ25
Microcin J25 (MccJ25) (98) is a 21-residue peptide of ribosomal is considered to be a model system in the rapidly emerging eld
origin isolated from E. coli. The peptide chain has an unusual of lasso peptides, as it was one of the rst discovered examples
‘lariat-protoknot’ structure, commonly referred to as a lasso for which a biosynthetic gene cluster was identied.595,860
peptide. MccJ25 is produced under stress-induced condi- The plasmid-encoded gene cluster is comprised of four
tions,859 and acts as an antimicrobial agent effective against genes, mcjA–D, encoding the precursor peptide (McjA),
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Fig. 22 (A) Enzymatic steps and the biosynthetic gene cluster involved in formation of microcin J25 (98), which resemble those involved in the
biosynthesis of other lasso peptides. (B) Structure of microcin J25 rendered from PDB: 1PP5. (C) Overlay of FhuA with microcin J25 (yellow/blue)
and ferrichrome (red) bound, showing common mode of binding leading to inhibitory activity of microcin J25. Structure generated from PDBs:
1FCP and 4CU4.
a cysteine protease (McjB), a lactam synthetase (McjC), and an binding of ferrichrome,866 allowing MccJ25 to successfully enter
ABC transporter (McjD) required for export (Fig. 22).595,862–864 the cell (Fig. 22). Interestingly, in the same study, the authors
Following ribosomal translation of McjA, the 58-amino acid observed no binding of capistruin (Fig. 20) (an antimicrobial
precursor peptide is processed by the ATP-dependent cysteine lasso peptide from B. thailandensis) in the binding site of FhuA,
protease McjB, which removes the leader peptide, yielding the and using molecular modelling they showed how capistruin ts
21-amino acids required for MccJ25 lasso formation.861,865 McjC into the ferrichrome binding region.866,867 These observations
acts to install an adenylate moiety on the Glu8 side chain, and explained MccJ25 import into the cell, but the more lethal target
subsequently catalyses isopeptide bond formation between the was later shown to be RNA polymerase (RNAP).868 Further in
NH2 of Gly1 and the activated Glu8 residue.861 In vitro studies vitro studies showed selective inhibition of Gram-negative
have shown that McjB-catalysed cleavage of the precursor RNAPs by both MccJ25 and capistruin, which is hypothesised
peptide is dependent upon ATP and McjC, indicative of complex to occur via blocking of the NTP-uptake channel.869,870
formation between the two enzymes.861 Once assembled in the MccJ25 also appears to possess an additional mode of action,
mature form, MccJ25 is exported from the cell via the ABC an effect observed on highly susceptible strains of Salmonella and
transporter protein McjD (Fig. 22).862 E. coli that overexpress FhuA. In these strains MccJ25 triggers
Efforts to establish the molecular target initially identied superoxide production via depolarisation of the cell membrane,
mutations in the TonB-dependent receptor FhuA in MccJ25- although the mechanism is currently unclear.871,872 Due to its
resistant clones. FhuA imports the iron-bound siderophore, outstanding stability towards proteases, heat and pH, MccJ25 has
ferrichrome. A recent crystal structure of FhuA with MccJ25 found potential therapeutic applications, and in a mouse model
bound reveals how the ring region of MccJ25 mimics the showed extended antimicrobial effects.873
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Fig. 23 Examples of other antimicrobial metabolites from Gram-negative bacteria.
6. Other 2011.123 Recent synthetic studies have elucidated the absolute

conguration of this metabolite, showing that the stereo-
Although most compounds discussed in this review can be cat- centres at C-2 and C-8 of the myristic acid-derived hydro-
egorised according to biosynthetic class, several antimicrobial carbon chain are R-congured.874 Alteration of either of these
metabolites from Gram-negative bacteria exist for which an stereocentres was shown to abolish bioactivity, highlighting
overarching biosynthetic classication is difficult to assign the important role played by the hydrogen-bonding network
(Fig. 23). Examples of such molecules include modied pyrroles within the compound (Fig. 24, highlighted in red).878 This led
and indoles, quinolones, b-lactams and carbapenems. In this to the discovery that promysalin functionally chelates Fe3+,
section, a selection of such metabolites with fascinating biosyn- suggesting that it may function as a siderophore.879 Together,
thetic pathways is highlighted. these studies have revealed the multifaceted role that 99 plays
in the rhizosphere which has led to a better understanding of
how the narrow spectrum of activity towards P. aeruginosa is
6.1 Promysalin achieved.
Promysalin (99) is a salicylate-containing natural product The promysalin BGC was reported alongside the discovery
produced by Pseudomonas putida RW10S1, isolated from the of the compound and a biosynthetic pathway based on char-
rhizosphere of rice plants.123 This compound exhibits activity acterised intermediates and shunt metabolites was proposed
against Pseudomonas aeruginosa strains, resulting in growth (Fig. 24).123 The promysalin core is constructed from myristic
inhibition at low mM concentrations. Promysalin is not active acid, proline and salicylic acid, where chorismic acid serves as
against Gram-positive bacteria.123 Mode-of-action studies have the precursor for the latter. PpgH and PpgG are responsible
shown that promysalin inhibits the production of the side- for producing salicylic acid from chorismic acid, and PpgM
rophore pyoverdine and dissipates established biolms.874 conjugates salicylic acid with coenzyme A. In parallel, L-
Promysalin biosynthesis is under control of the Gac/Rsm sig- proline is activated by PpgJ and loaded onto a carrier protein,
nalling pathway, a regulatory system that allows Pseudomonas for which PpgA is a likely candidate. PpgF, a putative Rieske
species to respond to environmental cues. This oen induces non-haem iron-dependent hydroxylase, installs a hydroxyl
the production of antagonistic compounds with a narrow group at C-8 of myristic acid. PpgC, PpgK and PpgE appear to
spectrum of activity.123,875–877 constitute a type II PKS, composed of ACP, KSa/KSb subunits,
The planar structure of promysalin and a model for its which appears to be responsible for myristic acid
biosynthesis were reported by De Mot and co-workers in biosynthesis.
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Fig. 24 Gene cluster and biosynthetic model for promysalin (99). Genes are annotated with proposed enzymatic functions. Steps for which
a gene has not been attributed are indicated with a dashed arrow. The atoms highlighted in red in promysalin (99) are thought to be involved in
Fe3+ binding.
The enzymatic activities responsible for the condensation Therefore, inhibition of glutamine synthetase leads to toxic
of 8-hydroxymyristic acid, proline and salicylic acid are intracellular levels of ammonia and ultimately chlorosis.887
currently unclear. However, detection of the prolyl ester of 8- The aminopeptidase responsible for conversion of tabtoxin
hydroxymyristic acid as a biosynthetic intermediate suggests to TbL is reliant upon the presence of zinc in the growth
that the C-8 hydroxyl group is installed prior to condensation medium, suggesting it is a zinc-dependent metal-
with salicylic acid. The order of the subsequent amidation lopeptidase.881,882 Self-resistance of P. syringae to TbL has been
(PpgO) and hydroxylation (PpgN) steps was deduced by attributed to adenylation of its glutamine synthetase, a modi-
targeted gene inactivation experiments. However, the timing cation which renders the enzyme less susceptible to inhibition
of the desaturation of the proline residue is currently by TbL.888 b-lactamases provide a second route for detoxica-
unknown, because the putative biosynthetic intermediates tion. These enzymes hydrolyse the b-lactam of TbL to yield
101–105, and the nal promysalin product (99) have all been tabtoxinine (109), which is non-toxic. P. syringae possesses three
detected. such enzymes.889,890 While the antimicrobial scope of TbL has
been largely unexplored, activity against Gram-positive (S.
6.2 Tabtoxin aureus) and Gram-negative (E. coli) bacteria has been
observed.891 Unlike most b-lactam antibiotics, TbL specically
Tabtoxin (106) is a monocyclic b-lactam produced by the
targets glutamine synthetase, an underexploited antimicrobial
phytopathogens Pseudomonas syringae pvs. tabaci, coronafaciens
target. Furthermore, TbL is produced by P. syringae in the form
and garcae. It is an exotoxin precursor of tabtoxinine b-lactam
of the prodrug, tabtoxin, which enters plant and bacterial cells
(TbL) (107), which is responsible for wildre disease in the
via dipeptide permeases. By virtue of this mode of action, TbL
tobacco plant Nicotiana tabacum.131,880–882
has been termed a ‘stealth’ b-lactam antibiotic, and may hold
Upon infection of the N. tabacum host, tabtoxin is secreted
promise as a starting point for the development of novel
and hydrolysed by an aminopeptidase to yield TbL, which
therapeutics.891
inhibits the plant glutamine synthetase.883,884 Glutamine
Structurally, tabtoxin is rather unique in that its b-lactam
synthetase is the primary mechanism for glutamine production
nitrogen atom is unfunctionalised.892 Furthermore, complete
in plant cells. Perhaps more importantly, however, the enzyme
structural and stereochemical assignment of the compound
plays a critical role in the detoxication of ammonia.885,886
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Fig. 25 Proposed biosynthetic pathway for tabtoxin (106) based on labelling studies. Additional steps in lysine biosynthesis are also shown,
indicating that 2-amino-6-oxopimelate (AOP) is a branch point in the pathways. The gene cluster implicated in tabtoxin biosynthesis is shown,
and the predicted function of each gene is given.
was challenging due to its inherent instability, arising from an the dapB gene is required for both DAP (precursor to lysine)
intramolecular transacylation, which yields the stable, but and tabtoxin production. 898 This observation also implies
inactive, d-lactam iso-tabtoxin (108).131,887,893 Extensive incor- that the pathway branch point lies aer formation of THDPA
poration experiments using isotope-labelled precursors have (Fig. 25). TabB is similar in sequence to N-succinyl-
identied likely precursors of tabtoxin.894–896 The C-3 side- transferases that catalyse the production of N-succinyl-2-
chain is derived from L-aspartate and L-threonine; C-3 and C- amino-6-oxopimelate (SAOP) in lysine biosynthesis, sug-
4 of the b-lactam ring come from pyruvate; and C-2 of the b- gesting that TabB might be an acetyltransferase.899 Interest-
lactam originates from L-methionine (Fig. 25). The tabtoxin ingly, TblA is required for tabtoxin formation, and is
BGC has been identied in P. syringae.897 Interestingly, the proposed to function as a SAM-dependent methyltransfer-
tabP gene encodes a putative zinc metallopeptidase, an excel- ase.900 It probably gives rise to the L -methionine-derived C-2
lent candidate for the hydrolase that converts tabtoxin to of the b-lactam. Formation of the b-lactam is catalysed
TbL.892 by TblS, a predicted b-lactam synthetase.892,901 Finally,
The proposed biosynthetic pathway for tabtoxin, consis- installation of the C-3 hydroxyl group is proposed to be
tent with labelling studies and predicted gene functions, is mediated by TblC, a 2-oxoglutarate (2OG)-dependent
outlined in Fig. 25. The initial stages of tabtoxin formation hydroxylase that forms the mature protoxin (106),894 from
overlap with lysine biosynthesis, and it has been shown that
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Fig. 26 Proposed pathway for C3C (110) biosynthesis. The car gene cluster from P. carotovorum is shown and the proposed function of each
gene is given. The b-lactam synthetase (CarA) and the carbapenem synthase (CarC) are highlighted in red and blue, respectively. The mecha-
nisms of the reactions catalysed by these enzymes are discussed in the text and shown in Fig. 27 and 28.
Fig. 27 (A) Proposed mechanism for CarA-catalysed b-lactam formation. Adenylation of the carboxylic acid followed by intramolecular
nucleophilic attack forms a tetrahedral intermediate. Subsequent collapse and elimination of AMP yields the b-lactam. (B) Crystal structure of
CarA (PDB: 1Q19) showing the largely helical C-terminal domain, and the two sets of anti-parallel b-sheets in the N-terminal domain. (C) Active
site of CarA (PDB: 1Q19), with the ‘trapped’ acyl-adenylate N2-(2-carboxymethyl)arginine-AMP (CMA-AMP) bound (PDB: 1MBZ). Reaction of ATP
with CMA yields CMA-AMP, which has one fewer carbons between the amino and carbonyl groups than the natural substrate. CMA-AMP is
unable to undergo cyclisation (indicated in red), because this would generate a highly strained alpha-lactam.
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Fig. 28 (A) Proposed mechanism for CarC-catalysed stereoinversion of (3S,5S)- to (3S,5R)-carbapenam-3-carboxylate (top), and subsequent
desaturation at C2–C3 via a radical intermediate at C2 (bottom). (B) Crystal structure of CarC (PDB: 1NX8) showing a double stranded b-helix fold,
common to many 2OG oxygenase enzymes. (C) Active site of CarC (PDB: 4OJ8) in complex with (3S,5S)-carbapenam-3-carboxylate (yellow).
Abstraction of Hc from C-5 of the substrate by the FeIV]O species generates a radical. Donation of Hc from Tyr165, positioned on the opposite
face of the substrate results in stereoinversion at C-5.
which compounds (107–109) can be formed via degradative present in more complex derivatives such as thienamycin,
processes (Fig. 25). semisynthetic derivatives of which have enjoyed extensive
application in the clinic. Understanding the intricacies of the
biosynthetic pathway to C3C may therefore offer opportunities
6.3 Carbapen-2-em-3-carboxylate (C3C) to generate novel carbapenem antibiotics via pathway
Carbapen-2-em-3-carboxylate (C3C) (110) is the simplest known engineering.
carbapenem. It was originally isolated from Pectobacterium The isolation of C3C from P. carotovorum led to identi-
carotovorum (formerly Erwinia) and Serratia species, and later cation of its biosynthetic gene cluster; the carA-H and carR,
identied as a metabolite of the insect pathogen Photorhabdus genes are believed to be involved in the biosynthesis of C3C
luminescens.612,902,903 It exhibits broad spectrum activity against and its regulation, respectively (Fig. 26).615,616,902 The expres-
Gram-positive and Gram-negative bacteria, including a b- sion of the carA-H gene cluster is regulated by CarR, a LuxR-
lactamase-producing Enterobacter cloacae strain. Despite its like transcriptional regulator that responds to N-(3-oxohex-
potent activity, C3C is extremely unstable and initially required anoyl)-L-homoserine lactone.904 CarF and CarG confer resis-
derivatization to the p-nitrobenzyl ester for isolation.612 While tance to C3C. However, the underlying mechanism is
C3C is not clinically useful, the carbapenem core scaffold is currently unknown.616 Recently, the crystal structure of CarG,
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which does not show homology to any known antibiotic biophysical experiments fully elucidated the epimerisation
resistance protein, was elucidated, revealing that it is mechanism.22 From the structural data, it is apparent that
a structural homologue of invertebrate lysozyme, Plil-Ah.905 It the FeIV]O species abstracts a hydrogen atom from C-5 of
has been proposed that CarD and CarE together catalyse the (3S,5S)-carbapenam, forming a C-5 radical. Donation of
initiating step of C3C biosynthesis. These enzymes mediate a hydrogen atom from the Tyr165 hydroxyl group to the
the oxidation of proline to yield L-glutamate semi-aldehyde (L- opposite face of this radical intermediate inverts the stereo-
GSA), which exists in equilibrium with L-5-hydroxyproline (L- chemistry at C-5, yielding (3S,5R)-carbapenam (Fig. 28). It is
5HP) and L-pyrroline-5-carboxylate (L-P5C), collectively worth noting that the Tyr165 residue could only be visualised
referred to as L-GHP (Fig. 26). It has been shown that CarA, with the natural substrate bound, due to the location of this
CarB and CarC are the minimal set of enzymes required for residue in a disordered loop region of CarC.919 The desatu-
C3C biosynthesis.906 CarB is a crotonase-like enzyme that ration mechanism likely proceeds via abstraction of
catalyses the formation of (2S,5S)-carboxymethylproline (t- a hydrogen atom from C-2, followed by abstraction of
CMP) from malonyl-CoA and L-P5C, the rst committed step a second hydrogen atom from C-3 in the resulting radical
in C3C biosynthesis.907,908 X-ray crystallographic studies of intermediate.
CarB have provided structural insights into its catalytic
mechanism.909 7. Conclusions and perspectives
CarA is a carbapenem synthetase which, in the presence of
ATP/Mg2+, catalyses closure of the b-lactam ring yielding (5S)- In recent years, Gram-negative bacteria have become
carbapenam-3-carboxylate.910,911 Crystallographic and increasingly recognized as a prolic source of antimicrobial
biochemical studies have provided insight into the catalytic natural products with therapeutic potential. Technological
cycle of this enzyme.910,912–914 Upon binding of t-CMP, CarA advances in genomics and molecular biology have greatly
catalyses the nucleophilic attack of the carboxymethyl group expanded our understanding of natural product biosyn-
on ATP to generate an adenylated intermediate, which then thesis in these versatile organisms and have revealed
undergoes a 4-exo-trig-cyclisation via a tetrahedral interme- a remarkable level of chemical diversity and biosynthetic
diate to form the b-lactam (Fig. 27). The crystal structure of ingenuity. While many biosynthetic pathways from Gram-
CarA from P. carotovorum shows it has a high degree of negative bacteria appear to have much in common with
structural homology to other b-lactam synthetases, exhibit- those of well-studied Actinobacteria and Bacillus species,
ing a largely helical C-terminal domain, and antiparallel b- they oen exhibit novel or atypical features, such as unusual
sheets in the N-terminal domain (Fig. 27).914 The crystal catalytic chemistry, or combinations of components from
structure of the homologous enzyme from Streptomyces different types of assembly line, resulting in hybrid path-
clavuligerus, containing the ‘trapped’ acyl-adenylate N2-(2- ways. The abundance and diversity of trans-AT PKS pathways
carboxymethyl)arginine-AMP (CMA-AMP) bound in the active in Gram-negative bacteria, compared with Actinobacteria
site, supports the proposed catalytic mechanism of CarA and other Gram-positive bacterial genera is particularly
(Fig. 27).912 striking. This suggests that trans-AT PKSs may have rst
CarC catalyses the nal two steps in C3C biosynthesis; a C- evolved in Gram-negative bacteria and later found their
5 stereoinversion of (3S,5S)- to (3S,5R)-carbapenam and way into selected Gram-positive bacteria via horizontal
subsequent C2–C3 desaturation to give C3C (110) (Fig. 28).915 transfer.
CarC is homologous to 2OG and non-haem iron-dependent Despite their proven potential to assemble antimicrobial
oxygenases, a class of enzymes for which desaturation specialized metabolites, the production of antibiotics by Gram-
chemistry has ample precedent.916 The C-5 stereoinversion negative bacteria remains understudied. Traditionally, drug
step, however, is unique to CarC.908 The structure of CarC discovery efforts in Gram-negatives have focused on pseudo-
reveals a double stranded b-helix fold, common to many 2OG monads, myxobacteria and cyanobacteria. However, the over-
and non-haem iron-dependent oxygenases (Fig. 28). In the whelming majority of microorganisms are difficult to isolate
same study, the structure of the N-acetyl-L-proline–CarC from the environment and/or cultivate under laboratory
complex was reported. N-Acetyl-L-proline mimics the (3S,5S)- conditions. The ongoing development and improvement of
carbapenam substrate of CarC, providing insights into the methods for cultivation of under- or unexplored microbial taxa,
mode of substrate binding.917 Furthermore, deuterium coupled with cultivation-independent approaches, such as
labelling experiments have demonstrated that the C-5 metagenomics, should afford access to the full biosynthetic
hydrogen is lost during CarC catalysis,918 and that the epi- potential of Gram-negative bacteria. The rapid development of
merised (3S,5R)-carbapenam can be released from the CarC new tools for the identication, genetic manipulation and
active site.892 Various mechanistic proposals arose from these heterologous expression of biosynthetic pathways will also
data, all of which involved radical intermediates. However, facilitate synthetic biology approaches aimed at establishing
until recently the source of the C-5 hydrogen was unclear. A efficient platforms for the creation of novel antibiotic
crystal structure of CarC in complex with (3S,5S)-carbapenam analogues. Future exploration and engineering efforts will thus
revealed that Tyr165 is the source hydrogen, and detailed greatly expand the arsenal of antibiotics known to be produced
by Gram-negative bacteria.
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Table 1 Comprehensive overview of antimicrobial metabolites known to be produced by Gram-negative bacteria
Compound Biosynthetic origin Producer(s) Bioactivity Molecular target Ref.
Pseudomonas
Mupirocin trans-AT PKS P. uorescens NCIMB 10586 Antibacterial Isoleucyl-tRNA 18–20
Antifungal synthetase
Furanomycin PKS P. uorescens SBW25 Antibacterial Isoleucyl-tRNA 21–23
Streptomyces threomyceticus synthetase
2,4- Type III PKS Pseudomonas sp. Antibacterial Proton gradient across 24–26
Diacetylphloroglucinol Lysobacter gummosus Antifungal the mitochondrial
Antihelmintic membrane
Phytotoxic
Antitumor
Brabantamide A NRPS Pseudomonas sp. Antibacterial Cell wall 27–32
Antifungal
Anti-oomycete
Obauorin NRPS P. uorescens SC12936 Antibacterial Unknown 33 and 34
Aeruginaldehyde NRPS P. uorescens Antifungal Unknown 35
Burkholderia cepacia
Safracins NRPS P. uorescens Antibacterial DNA 36–39
Antitumor
Syringomycin E NRPS P. syringae Antibacterial Cell membrane 40–43
Antifungal
Hemolytic
Phytotoxic
Thanamycin NRPS P. uorescens DSM11579 Antifungal Unknown 44 and 45
Pseudomonas sp. SH-C52
Thanapeptin NRPS Pseudomonas sp. SH-C52 Antibacterial Unknown 45
Anti-oomycete
Xantholysins NRPS P. putida BW11M1 Antibacterial Unknown 46 and 47
Antifungal
Hemolytic
Biosurfactant
Poaeamide A and B NRPS P. poae RE*1-1-14 Antifungal Unknown 48 and 49
P. synxantha CR32 Anti-oomycete
Biosurfactant
Putisolvin I and II NRPS P. putida Antifungal Unknown 50 and 51
Anti-oomycete
Biosurfactant
Cormycin NRPS P. corrugata CFBP 5454 Antibacterial Cell membrane 52 and 53
Phytotoxic
Hemolytic
Massetolide A and B NRPS P. uorescens SS101 Antibacterial Cell membrane 54–56
Anti-oomycete
Anti-protozoan
Biosurfactant
WLIP NRPS P. uorescens Antibacterial Cell membrane 57–60
P. putida Antifungal
Hemolytic
Amphisin NRPS Pseudomonas sp. DSS73 Antifungal Unknown 59 and 61
Anti-oomycete
Biosurfactant
Viscosin NRPS P. uorescens Antibacterial Unknown 59 and 62
Anti-oomycete
Antiviral
Antiprotozoal
Biosurfactant
Corpeptin A and B NRPS P. corrugata CFBP 5454 Antibacterial Unknown 53 and 63
Phytotoxic
Syringopeptin SP25A NRPS P. syringae Antibacterial Cell membrane 64–68
Antifungal
Phytotoxic
Cytotoxic
Syringopeptins NRPS P. syringae Antibacterial Cell membrane 68–70
SP22A and B Antifungal
SP508A and B Phytotoxic
Biosurfactant
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Table 1 (Contd. )
Tolaasin I NRPS P. tolaasii Antibacterial Cell membrane 71–74

P. costantinii Antifungal
Phytotoxic
Hemolytic
Sessilin NRPS Pseudomonas CMR12a Antifungal Unknown 75 and 76
Phytotoxic
Orfamide A NRPS P. protegens Antifungal Unknown 77 and 78
Anti-oomycete
Anti-insecticidal
Biosurfactant
Nunamycin NRPS P. uorescens Antifungal Unknown 79
Nunapeptin NRPS P. uorescens Antifungal Unknown 79
Indigoidine NRPS P. indigofera Antibacterial Unknown 80–87
Phaeobacter sp. Y4I Antifungal
Leisingera sp. JC1
Photorhabdus luminescens
Dickeya dadantii
Erwinia chrysanthemi
Streptomyces sp.
Corynebacterium insidiosum
Arthrobacter sp.
L-2-Amino-4-methoxy- NRPS P. aeruginosa Antibacterial PLP-dependent 88 and 89
trans-3-butenoic acid Cytotoxic enzymes
Micacocidin Hybrid iterative type I Pseudomonas sp. no. 57-250 Antibacterial Unknown 90 and 91
PKS/trans-AT PKS/NRPS Ralstonia solanacearum Antifungal
GMI1000
Andrimid Hybrid type II PKS/trans- P. uorescens Antibacterial Acetyl-CoA carboxylase 92–96
AT Enterobacter cloacae
PKS/NRPS Vibrio coralliilyticus
Pantoea agglomerans
Serratia sp.
Moiramide B Hybrid type II PKS/trans- P. uorescens Antibacterial Acetyl-CoA carboxylase 97 and 98
AT PKS/NRPS Vibrio sp.
Kalimantacin Hybrid trans-AT PKS– Pseudomonas sp. Antibacterial FabI 99–101
A/batumin NRPS Alcaligenes sp. YL-02632S
Pyoluteorin Hybrid PKS–NRPS Pseudomonas sp. Antibacterial Unknown 102 and
Anti-oomycete 103
Rhizoxin analogs Hybrid trans-AT PKS/ P. protegens Pf-5 Antifungal b-Tubulin 104
NRPS Anti-oomycete
Phytotoxic
Insecticidal
Antitumor
Bactobolin A–C Hybrid PKS–NRPS Pseudomonas sp. BMG13- Antibacterial L2 protein 105 and
A7 Antitumor 106
F-Type pyocins RiPP P. aeruginosa Antibacterial Unknown 107
R-Type pyocins RiPP P. aeruginosa Antibacterial Cell membrane 108
Pyocins S1, S2, S3, AP41 RiPP P. aeruginosa Antibacterial DNA 109–112
Pyocin S4 RiPP P. aeruginosa Antibacterial tRNA 113
Pyocin S5 RiPP P. aeruginosa Antibacterial Cell membrane 114
Pyocins S6, S7 RiPP P. aeruginosa Antibacterial rRNA 115 and
116
Pyocins M1 RiPP P. aeruginosa Antibacterial Lipid II 117
2-Hexyl-5- FAS Pseudomonas sp. Antibacterial Unknown 89
propylresorcinol Antifungal
Pyrrolnitrin Other Pseudomonas sp. Antibacterial Respiratory electron 118–122
Serratia sp. transport system
Burkholderia sp.
Pantoea agglomerans
Myxococcus fulvus Antifungal
Promysalin Other P. putida RW10S1 Antibacterial Unknown 123
Pseudopyronines A and Other Pseudomonas sp. Antibacterial Cell membrane 124–126
B Alteromonas sp. KNS-16 Anti-parasitic FAS II (FabG/FabI/InhA)
View Article Online
Table 1 (Contd. )
Algicidal
Cytotoxic
Antifungal
2-Heptyl-4- Other P. aeruginosa Antibacterial Cytochrome b 127 and
hydroxyquinoline- Burkholderia pseudomallei Cytotoxic 128
N-oxide
2-n-Pentyl-4-quinolinol Other P. bromoutilis Antibacterial Unknown 129 and
Alteromonas strain SWAT5 Algicidal 130
2-n-Heptyl-4-quinolinol Other P. aeruginosa Antibacterial Unknown 129 and
P. bromoutilis 130
Alteromonas strain SWAT5
Tabtoxin Other P. syringae Antibacterial Glutamine synthetase 131–133
Phytotoxic
Pyocyanin Other Pseudomonas sp. Antibacterial Cell membrane 134 and
Antifungal respiratory chain 135
Antiprotozoal
Cytotoxic
Phenazine-1-carboxylic Other Pseudomonas sp. Antibacterial Generation of reactive 136 and
acid Antifungal oxygen species 137
Cytotoxic
Thiotropocin Other Pseudomonas sp. CB-104 Antibacterial Unknown 138–141
Roseobacter strain 27-4 Antifungal
Antiprotozoal
Magnesidin A Unknown Pseudomonas Antibacterial Unknown 142–144
magnesiorubra
V. gazogenes Anti-algal
Aerugine Unknown Pseudomonas sp. Antifungal Unknown 145 and
Streptomyces fradiae Anti-oomycete 146
Cyclo (L-Pro-L-Tyr) Unknown Pseudomonas sp. Antibacterial Unknown 147–151
L. capsici AZ78 Antifungal
Aristabacter necator 679-2 Anti-oomycete
Streptomyces sp. strain 22-4
Oxazinomycin Unknown Pseudomonas sp. SC 11793 Antibacterial Unknown 152 and
Streptomyces sp. Antitumor 153
Sclerosin Unknown Pseudomonas sp. DF41 Antibacterial Unknown 154
Antifungal
Plusbacin A3 Unknown Pseudomonas sp. PB-6250 Antibacterial Peptidoglycan 155 and
156
Ecomycins A–C Unknown P. viridiava Antifungal Unknown 157
Pseudophomin A and B Unknown P. uorescens BRG100 Antifungal Cell membrane 158 and
Phytotoxic 159
Pseudodesmin A and B Unknown P. tolaassii Antibacterial Cell membrane 160 and
Antiviral 161
Cytotoxic
Lokisin Unknown Pseudomonas sp. DSS41 Antifungal Unknown 162
P. uorescens CTS41 Biosurfactant
Tensin Unknown P. uorescens Antifungal Unknown 163 and
Biosurfactant 164
Syringostatin A Unknown P. syringae Antifungal Cell membrane 165 and
Phytotoxic 166
Cytotoxic
Syringotoxin B Unknown P. syringae Antibacterial Cell membrane 167 and
Antifungal 168
Phytotoxic
Cytotoxic
Pseudomycins Unknown P. syringae Antifungal Cell membrane 169 and
Phytotoxic 170
Cytotoxic
Fuscopeptins Unknown Pseudomonas fuscovaginae Antifungal Cell membrane 171–173
Phytotoxic
Hemolytic
Viscosinamide Unknown P. uorescens DR54 Antifungal Fungal membranes 174–176
View Article Online
Table 1 (Contd. )
Anti-oomycete
Biosurfactant
Myxobacteria
Ambruticins cis-AT PKS Sorangium cellulosum So Antifungal Osmoregulation 177 and
ce10 via HOG pathway 178
Aurafurons cis-AT PKS Stigmatella aurantiaca Antifungal Unknown 179
Archangium gephyra Cytotoxic
Gephyronic acid cis-AT PKS A. gephyra Ar3895 Antifungal Protein synthesis 180 and
Cystobacter violaceus Cb Cytotoxic 181
vi76
Haliangicin cis-AT PKS Haliangium sp. Antifungal Respiration complex III 182–184
Cytotoxic
Gulmirecins cis-AT PKS Pyxidicoccus fallax Antibacterial Unknown 185
Disciformycins cis-AT PKS P. fallax Antibacterial Unknown 186
Jerangolids cis-AT PKS S. cellulosum Antifungal Cell membrane 187 and
188
Soraphen cis-AT PKS S. cellulosum So ce26 Antifungal Acetyl-CoA carboxylase 189–194
Anticancer
Antiviral
Spirangien cis-AT PKS S. cellulosum So ce90 Antifungal Unknown 195–198
Cytotoxic
Antiviral
Stigmatellin cis-AT PKS S. aurantiaca Antifungal Respiration complex I 199 and
200
Thuggacin cis-AT PKS S. cellulosum So ce895 Antibacterial Respiration chain 201–203
Chlorotonil trans-AT PKS S. cellulosum So ce1525 Antibacterial Unknown 204–206
Antiprotozoal
Antifungal
Disorazol trans-AT PKS S. cellulosum So ce12 Antifungal Tubulin 207–209
Cytotoxic
Etnangien trans-AT PKS S. cellulosum Antibacterial RNA polymerase 210 and
Antiviral 211
Sorangicin trans-AT PKS S. cellulosum Antibacterial RNA polymerase 212–214
Eliamid PKS S. cellulosum Antifungal Mitochondrial 215
Antihelmintic respiratory
Cytotoxic complex I
Hyapyrones PKS Hyalangium minutum Antibacterial Unknown 216
Antifungal
Icumazole PKS S. cellulosum So ce701 Antifungal NADH oxidation 217
Roimatacene PKS Cystobacter ferrugineus Cb Antibacterial Unknown 218
G35
Argyrin NRPS A. gephyra Antibacterial Elongation factor G 219 and
Antifungal 220
Cytotoxic
Anti-inammatory
Cystobactamids NRPS Cystobacter sp. Cbv34 Antibacterial Type II topoisomerase 221
Saframycin Mx1 NRPS Myxococcus xanthus Antibacterial DNA 222–225
DM504/15 Antitumor
Ajudazol Hybrid cis-AT Chondromyces crocatus Cm Antifungal Unknown 226 and
PKS/NRPS c5 Antibacterial 227
Althiomycin Hybrid cis-AT PKS/NRPS M. xanthus Antibacterial Peptidyltransferase 228–232
Serratia marcescens Db10
Cystobacter fuscus
Streptomyces althioticus
Bengamides Hybrid cis-AT PKS/NRPS Myxococcus virescens Antibacterial Methionine 233–238
ST200611 Antihelmintic aminopeptidases
Cytotoxic
Anti-inammatory
Chondramides Hybrid cis-AT PKS/NRPS C. crocatus Cm c5 Antifungal Actin cytoskeleton 239–243
Cytotoxic
Antitumor
Antiparasitic
View Article Online
Table 1 (Contd. )
Chondrochloren Hybrid cis-AT PKS/NRPS C. crocatus Cm c5 Antibacterial Unknown 244 and

Antifungal 245
Crocacin Hybrid cis-AT PKS/NRPS C. crocatus Cm c5 Antifungal Respiration complex III 246 and
Cytotoxic 247
Epothilone Hybrid cis-AT PKS/NRPS S. cellulosum Antifungal Tubulin 248–252
Cytotoxic
Leupyrrin Hybrid cis-AT PKS/NRPS S. cellulosum So ce690 Antifungal DNA, RNA and 253 and
Cytotoxic protein synthesis 254
Macyranones Hybrid cis-AT PKS/NRPS C. fuscus MCy9118 Antifungal Proteasome 255
Antiparasitic
Cytotoxic
Melithiazol Hybrid cis-AT PKS/NRPS Melittangium Antifungal Respiration complex III 256 and
lichenicola Me l46 Cytotoxic 257
Microsclerodermin Hybrid cis-AT PKS/NRPS Jahnella sp. Antifungal Unknown 258 and
D and L Chondromyces sp. Antitumor 259
Microsclerodermin M Hybrid cis-AT PKS/NRPS Sorangium sp. Antifungal Unknown 258
Myxalamid Hybrid cis-AT PKS/NRPS S. aurantiaca Sga15 Antifungal Respiration complex I 260–262
Myxothiazol Hybrid cis-AT PKS/NRPS S. aurantiaca DW4/3-1 Antifungal Respiration complex III 263–266
Cytotoxic
Nannocystin Hybrid cis-AT PKS/NRPS Nannocystis sp. Antifungal Translation elongation 267 and
Cytotoxic factor 1a 268
Pedein Hybrid cis-AT PKS/NRPS Chondromyces Antifungal Cell membrane 269
pediculatus Cm p3 Cytotoxic
Corallopyronin Hybrid trans-AT PKS/ Corallococcus coralloides Antibacterial RNA polymerase 270–272
NRPS
Myxopyronin Hybrid trans-AT PKS/ M. fulvus Mx f50 Antibacterial RNA polymerase 273–275
NRPS
Myxovirescin Hybrid NRPS/trans-AT Myxococcus sp. Antibacterial Type II signal peptidase 276–279
PKS LspA
Rhizopodin Hybrid trans-AT PKS/ S. aurantiaca Sg a15 Antifungal Actin cytoskeleton 280–283
NRPS M. stipitatus Cytotoxic
Ripostatin Hybrid cis-/trans-AT PKS S. cellulosum So ce 377 Antibacterial RNA polymerase 284 and
Antifungal 285
Indiacens Other Sandaracinus amylolyticus Antibacterial Unknown 286
Antifungal
Pyrrolnitrin Other M. fulvus Antibacterial Respiratory electron 118–122
Pseudomonas sp. Antifungal transport system
Serratia sp.
Burkholderia sp.
Pantoea agglomerans
Aetheramide Unknown Aetherobacter rufus SBSr00 Antifungal Unknown 287
Antiviral
Cytotoxic
Angiolam Unknown Angiococcus disciformis An Antibacterial Protein synthesis 288
d30
Apicularen Unknown Chondromyces sp. Antibacterial Vacuolar ATPases 289–292
Cytotoxic Microtubuli
Aurachin Unknown S. aurantiaca Sg a15 Antibacterial Respiration 293–295
Antifungal complex I and III
Carolacton Unknown S. cellulosum So ce960 Antibacterial Serine/threonine 296 and
protein kinase PknB 297
(PKS, paper Biolm formation
coming out)
Cruentaren Unknown Byssovorax cruenta Antifungal Mitochondrial F0F1- 298–300
Cytotoxic ATPase
Cyrmenin Unknown Cystobacter armeniaca Antifungal Respiration complex III 301 and
A. gephyra Cytotoxic 302
Cystothiazole Unknown C. fuscus Antifungal Respiration complex III 303 and
Cytotoxic 304
Enhygrolide Unknown Enhygromyxa salina Antibacterial Unknown 305
Indiacen Unknown Sandaracinus amylolyticus Antibacterial Unknown 286
NOSO-4T Antifungal
View Article Online
Table 1 (Contd. )
Hyaladione Unknown Hyalangium minutum Antibacterial Unknown 306

NOCB-2T Antifungal
Cytotoxic
Maracin/Maracen Unknown S. cellulosum Antibacterial Unknown 307
Miuraenamide Unknown Paraliomyxa miuraensis Antifungal Respiration complex III 308 and
SMH-27-4 309
Myxocoumarins Unknown S. aurantiaca MYX-03 Antifungal Unknown 310
Myxovalargin Unknown M. fulvus Antibacterial Protein synthesis 311 and
Cytotoxic Cell membrane 312
Antiprotozoal
Nannozinone A Unknown Nannocystis pusilla Antibacterial Unknown 313
MNA10913 Antifungal
Phenoxan Unknown Polyangium sp. Antifungal Respiration complex I 314
Pyrronazol A Unknown Nannocystis pusilla Ari7 Antifungal Unknown 315
Ratjadone Unknown S. cellulosum Antifungal Exportin 1 (CMR1) 316–318
Cytotoxic
Antiviral
Salimabromide Unknown E. salina Antibacterial Unknown 319
Sorangiadenosine Unknown S. cellulosum KM1003 Antibacterial Unknown 320
Sorangiolid Unknown S. cellulosum So ce12 Antibacterial Cell membrane 321
Sorazinones A and B Unknown S. cellulosum So ce895 Antibacterial Unknown 313
Salimyxin B Unknown E. salina Antibacterial Unknown 305
Enhygrolide A Unknown E. salina Antibacterial Unknown 305
Cyanobacteria
Kasumigamide Hybrid cis-AT Microcystis aeruginosa Antialgal Unknown 322 and
PKS/NRPS Entotheonella sp. 323
Kawaguchipeptin B RIPP M. aeruginosa Antibacterial Unknown 324
Dudawalamide A NRPS Lyngbya sp. Antiparasitic Unknown 325
Carmabins Hybrid PKS–NRPS Lyngbya majuscula Antiprotozoal Unknown 326
Companeramides A–B NRPS Leptolyngbya sp. Antiprotozoal Unknown 327
Pitipeptolides A–C, F Hybrid PKS–NRPS L. majuscula Antimicrobial Unknown 328 and
329
Dragonamides A–C, E Hybrid PKS–NRPS Lyngbya sp. Antiparasitic Unknown 330 and
331
Dragomabin Hybrid PKS–NRPS L. majuscula Antiparasitic Unknown 332
Viridamides A–B Hybrid PKS–NRPS Oscillatoria nigro-viridis Antiparasitic Unknown 333
Almiramide A Hybrid PKS–NRPS L. majuscula Antiparasitic Membrane 334 and
assembly 335
machinery
Norharmane Other Nodularia harveyana Antibacterial Unknown 336–339
Antifungal
Algicidal
4,40 -Dihydroxybiphenyl Unknown Nostoc insulare Antibacterial Unknown 336–339
Antifungal
Algicidal
Noscomin Other Nostoc commune Antibacterial Unknown 340
Carbamidocyclophanes Hybrid type I– Nostoc sp. Antibacterial Unknown 341–343
type III PKS Antifungal
Cytotoxic
Ambiguine isonitriles Other Fischerella sp. Antibacterial Unknown 344–346
Cytotoxic
Norbietanes Other Microcoleus lacustris Antibacterial Unknown 347
Hapalindoles Other Fischerella sp. Antibacterial Unknown 346 and
Cytotoxic 348
Insecticidal
Pahayokolide A Hybrid PKS–NRPS Lyngbya sp. Antibacterial Unknown 349–351
Antifungal
Algicidal
Antitumor
Venturamides Unknown Oscillatoria sp. Antiprotozoal Unknown 352
Ambigol C Unknown F. ambigua Antiprotozoal Unknown 353
View Article Online
Table 1 (Contd. )
Kalkipyrone B PKS Leptolyngbya sp. Antifungal Unknown 354

Cytotoxic
Malyngolide Unknown Moorea producens Antiprotozoal Interference 355–357

Cytotoxic with bacterial
quorum sensing
Scytoscalarol Other Scytonema sp. Antibacterial Arabinosyltransferase 358 and
Antifungal 359
Eucapsitrione Eucapsis sp. Antibacterial Unknown 360
Nostocarboline Other Nostoc Antibacterial Inhibits 361–364
acetylcholinesterase
and trypsin
Algicidal Membrane damage
Antiparasitic
Aeruginazole A NRPS Microcystis sp. Antibacterial Unknown 365 and
Antifungal 366
Cytotoxic
Bromoanaindolone Unknown Anabaena constricta Antibacterial Unknown 367
Carriebowlinol Other Cyanobacteria, unclassied Antibacterial Unknown 368
Antifungal
Comnostins Other Nostoc commune Antibacterial Unknown 369
Cytotoxic
Crossbyanol A–C Other Leptolyngbya crossbyna Antibacterial Unknown 370
a-Dimorphecolic FAS Oscillatoria redekei Antibacterial Unknown 371
and coriolic acid
Lyngbyazothrins C and NRPS Lyngbya sp. Antibacterial 20S proteasome 372 and
D 373
Malyngamides Unknown L. majuscula Antibacterial Interfere with 374–381
quorum sensing
Cytotoxic Target MyD88-
dependent
pathway
Muscoride A Unknown Nostoc muscorum Antibacterial Unknown 382
Nostocyclyne A PKS Nostoc sp. Antibacterial Unknown 383
Schizotrin A NRPS Schizothrix sp. Antibacterial Unknown 384
Antifungal
Balticidins NRPS Anabaena cylindrical Antifungal Unknown 385
Calophycin Unknown Calothrix fusca Antifungal Unknown 386
Fischerellin A Unknown Fischerella muscicola Antifungal Photosystem II 387–389
Antialgal
Herbicidal
Hassallidins A and B NRPS Hassallia sp. Antifungal Unknown 390
Cytotoxic
Laxaphycins NRPS Anabaena sp. Antifungal Unknown 391–394
Moorea producens Cytotoxic
Lobocyclamide A–D NRPS Lyngbya confervoides Antifungal Unknown 395
Lyngbyabellins A and B Unknown L. majuscula Antifungal Actin 396 and
M. producens Cytotoxic 397
Majusculamide C Unknown L. majuscula Antifungal Unknown 398
Moorea producens Cytotoxic
Majusculoic acid Unknown Undened cyanobacteria Antifungal Unknown 399
Nostofungicidine Unknown Nostoc commune Antifungal Unknown 400
Cytotoxic
Scytophycins trans-AT PKS Scytonema sp. Antifungal Actin-binding 401–404
Cytotoxic
Tolytoxins trans-AT PKS Tolypothrix sp. Antifungal Actin-binding 403–405
Cytotoxic
Tanikolide Unknown Lyngbya majuscula Antifungal Unknown 406 and
Moorea producens 407
Tolybyssidins A/B Unknown Tolypothrix byssoidea Antifungal Unknown 408
Bastimolide A Unknown Okeania hirsuta Antiprotozoal Unknown 409
Companeramides Unknown Undened cyanobacterial Antiprotozoal Unknown 410
A and B collection
View Article Online
Table 1 (Contd. )
Coibacins PKS Oscillatoria sp. Antiprotozoal Unknown 411 and

412
Hectochlorin A Hybrid PKS/NRPS Lyngbya majuscula Antifungal Actin 413

Moorea sp. Cytotoxic
Lysobacter
2,4- Type III PKS Lysobacter gummosus Antibacterial Proton gradient across 24–26
Diacetylphloroglucinol Pseudomonas sp. Antifungal the mitochondrial
Antihelmintic membrane
Phytotoxic
Antitumor
Tripropeptins NRPS Lysobacter sp. Antibacterial Undecaprenyl 414–417
Collimonas fungivorans pyrophosphate
Lysobactin/katanosin B NRPS Lysobacter sp. Antibacterial Lipid II 418–421
Cytophaga strain PBJ-5356
WAP-8294A NRPS Lysobacter sp. Antibacterial Cell membrane 422 and
phospholipids 423
Lysocins NRPS Lysobacter sp. RH2180-5 Antibacterial Menaquinone in the 424–426
cell membrane
Heat stable antifungal Hybrid iterative type I Lysobacter sp. Antifungal Ceramide synthase, 427–429
factor PKS/NRPS sphingolipid
(HSAF)/ biosynthesis
dihydromaltophilin tubulin
Induction of fungal
apoptosis
through ROS
accumulation
Alteramide A Hybrid iterative type I L. enzymogenes Antifungal Unknown 430 and
PKS/NRPS Alteromonas sp. Cytotoxic 431
P. piscicida 0T59
Lysobacteramide B Hybrid iterative type I L. enzymogenes Antifungal Unknown 431
PKS/NRPS Cytotoxic
Cephabacins Hybrid PKS–NRPS L. lactamgenus YK90 Antibacterial Penicillin-binding 432–434
proteins
Myxin Other L. antibioticus OH13 Antibacterial DNA 435–437
Cytotoxic
Cyclo (L-Pro-L-Tyr) Unknown L. capsici AZ78 Antibacterial Unknown 147–151
Aristabacter necator 679-2 Antifungal
Pseudomonas sp. Anti-oomycete
Xanthobaccins Unknown Lysobacter sp. SB-K88 Antifungal Mycelial growth 438 and
Stenotrophomonas sp. Anti-oomycete inhibition and 439
strain SB-K88 zoospore lysis
Lactivicin Unknown L. albus YK-422 Antibacterial Penicillin-binding 440–442
Empedobacter lactamgenus proteins
YK-258
Burkholderia
Aeruginaldehyde NRPS B. cepacia Antifungal Unknown 35
P. uorescens
Caryoynencin PKS B. caryophilli Antibacterial Unknown 443–445
Antifungal
Bongkrekic acid trans-AT PKS B. gladioli Antibacterial Mitochondrial adenine 446 and
Antifungal nucleotide translocator 447
Cytotoxic
Gladiolin trans-AT PKS B. gladioli Antibacterial RNA polymerase 448
Antifungal
Malleilactone/ trans-AT PKS B. thailandensis Antibacterial Iron(III) chelation 449 and
Burkholderic Cytotoxic 450
acid
Bactobolins A–H Hybrid cis-AT B. thailandensis Antibacterial Ribosome 105, 451
PKS/NRPS B. ambifaria and 452
View Article Online
Table 1 (Contd. )
Burkholdines Hybrid cis-AT B. ambifaria Antifungal Unknown 453 and

PKS/NRPS Hemolytic 454
Enacyloxin IIa Hybrid cis-/trans-AT Burkholderia sp. Antibacterial Elongation factor Tu 455–457
PKS/NRPS Frateuria sp. W-315
Glidobactins Hybrid PKS–NRPS Burkholderia sp. Antifungal Proteasome 458 and
P. luminescens TTO1 Cytotoxic 459
P. asymbiotica ATCC43949
Occidiofungin Hybrid cis-AT B. contaminans Antifungal Unknown 460–462
PKS/NRPS
Rhizoxin Hybrid trans-AT B. rhizoxina Antifungal Microtubuli 104, 463
PKS/NRPS Phytotoxic and 464
Antimitotic
Capistruin RiPP B. thailandensis Antibacterial RNA polymerase 465–467
2-Heptyl-4- Other B. pseudomallei Antibacterial Cytochrome b 127 and
hydroxyquinoline-N- P. aeruginosa Cytotoxic 128
oxide
Pyrrolnitrin Other Burkholderia sp. Antibacterial Respiratory electron 118–122
Serratia sp.
Pantoea agglomerans
Myxococcus fulvus
Cepacins A, B Unknown B. cenocepacia Antibacterial Unknown 468
Cepafungin I Unknown B. cepacia Antifungal Proteasome 459 and
P. luminescens Cytotoxic 469
Xenorhabdus
Xenematide NRPS X. nematophila Antibacterial Unknown 470–472
Insecticidal
Xenorhabdins 1–3 NRPS X. nematophila Antibacterial RNA polymerase 473 and
X. bovienii Antifungal 474
Insecticidal
Cytotoxic
Bicornutin NRPS X. budapestensis Anti-oomycete Unknown 475
GameXpeptides NRPS Xenorhabdus strains Antiprotozoal Unknown 476–478
P. luminescens TTO1
PAX peptides NRPS X. nematophila Antibacterial Unknown 479
X. caballinasii Antifungal
Xenoamicins NRPS Xenorhabdus sp. Antiprotozoal Unknown 474 and
478
Rhabdopeptides NRPS X. nematophila Antiprotozoal Unknown 480
X. cabanillasii Insecticidal
Cytotoxic
Xenortides NRPS X. nematophila Antiprotozoal Unknown 470 and
481
Xenocoumacins Hybrid cis-AT X. nematophila Antibacterial Arginyl-tRNA 482–484
PKS/NRPS Antifungal synthetase
Antiulcer
Amicoumacins Hybrid cis-AT X. bovienii Antibacterial Ribosome (E-site) 485–487
PKS/NRPS Bacillus sp. Cytotoxic
Nocardia sp. Anti-inammatory
Anti-ulcer
Fabclavines Hybrid PUFA X. budapestensis Antibacterial Unknown 488
synthase-like X. szentirmaii Antifungal
assembly line/cis-AT Antiprotozoal
PKS/NRPS Cytotoxic
Xenorhabdicin RiPP X. nematophila Antibacterial Membrane 489 and
490
Xenocin RiPP X. nematophila Antibacterial Unknown 491
Xenobovides Unknown X. bovienii Antibacterial Unknown 492
Antitumor
Insecticidal
Cabanillasin Unknown X. cabanillasii Antifungal Unknown 493
Nemaucins Unknown X. caballinasii Antibacterial Unknown 494
View Article Online
Table 1 (Contd. )
Nematophin Unknown X. nematophila Antibacterial Unknown 495–497

Antifungal
Xenorxides Unknown X. bovienii Antibacterial Unknown 498

Antifungal
Cytotoxic
Szentiamide Unknown X. szentirmaii Antiprotozoal Unknown 499 and
500
Xenobactin Unknown Xenorhabdus sp. PB30.3 Antibacterial Unknown 501
Antiprotozoal
Benzylideneacetone Unknown X. nematophila Antibacterial Unknown 502
Immunosuppressant
Photorhabdus
Lumiquinone A PKS P. luminescens TT01 Antibacterial Unknown 503
Antifungal
3,5-Dihydroxy-4-ethyl- PKS P. luminescens Antibacterial Inhibition of RNA 504
trans-stilbene Bacillus cereus Antifungal synthesis via an
increase in ppGpp
concentration
3,5-Dihydroxy-4- PKS P. luminescens Antibacterial Unknown 504
isopropyl- Bacillus sp. Antifungal
trans-stilbene Nematicidal
Insecticidal
Indigoidine NRPS P. luminescens Antibacterial Unknown 80–87
Pseudomonas indigofera Antifungal
Phaeobacter sp. Y4I
Leisingera sp. JC1
Dickeya dadantii
Erwinia chrysanthemi
Streptomyces sp.
Arthrobacter sp.
GameXpeptides NRPS P. luminescens TTO1 Antiprotozoal Unknown 476–478
Xenorhabdus strains
Glidobactins Hybrid PKS–NRPS P. luminescens TTO1 Antifungal Proteasome 458 and
P. asymbiotica ATCC43949 Cytotoxic 459
Burkholderia sp.
Photorhabdicins RiPP Photorhabdus sp. Antibacterial Unknown 505
Benzaldehyde Other P. temperata M1021 Antibacterial Cell membrane 506
Antifungal
Insecticidal
Antioxidant
Cepafungin I Unknown P. luminescens Antifungal Proteasome 459 and
Burkholderia cepacia Cytotoxic 469
Vibrio
Vitroprocines PKS Vibrio sp. QWI-06 Antibacterial Unknown 507
Andrimid Hybrid type II Vibrio coralliilyticus Antibacterial Acetyl-CoA carboxylase 92–96
PKS/trans-AT P. uorescens
PKS/NRPS Enterobacter cloacae
Pantoea agglomerans
Serratia sp.
Moiramide B Hybrid type II Vibrio sp. Antibacterial Acetyl-CoA carboxylase 97 and 98
PKS/NRPS
Prodigiosin Hybrid cis-AT Vibrio sp. Antibacterial DNA cleavage 508–512
PKS/NRPS/other (Pseudo)Alteromonas rubra Antifungal
Serratia sp.
Hahella chejuensis
Streptomyces sp.
Cycloprodigiosin Hybrid PKS– V. gazogenes Antibacterial F-ATPases 511 and
NRPS/other (Pseudo)Alteromonas rubra Inhibition of protein 513
synthesis
View Article Online
Table 1 (Contd. )
Turbomycin A and B Other Vibrio sp. Antibacterial Unknown 514

S. cerevisiae Antifungal
Pelagiomicin Other Vibrio sp. Antibacterial Unknown 515

C/glycylgriseoluteic Microbulbifer variabilis Antitumor
acid
D-Alanylgriseoluteic Other Vibrio sp. SANK 73794 Antibacterial Induction of SOS 516 and
acid Pantoea agglomerans respons and redox 517
Eh1087 activity
Magnesidin A Unknown V. gazogenes Antibacterial Unknown 142–144
P. magnesiorubra Antialgal
3,5-Dibromo-2-(30 ,50 - Unknown Vibrio sp. Antibacterial Cell membrane 518
dibromo-20 -methoxy- Antifungal
phenoxy)-phenol
Vibrindole A Unknown V. parahaemolyticus Antibacterial Unknown 519
Streptomyces sp. Antifungal
Symbiobacterium Antitumor
thermophilum IAM14863
Kahalalides Unknown V. mediterranei Antibacterial Plasma membrane 520
Elysia rufescens Antiprotozoal
Bryopsis pennata Antiviral
Antifungal
Antitumor
Aqabamycins Unknown Vibrio sp. Antibacterial Unknown 521
Antitumor
Trisindoline Unknown V. parahaemolyticus Bio249 Antibacterial Unknown 522
Rubrivivax benzoatilyticus Cytotoxic
JA2
Isatis costata
Pseudoalteromonas
Alteramide A Hybrid iterative P. piscicida 0T59 Antifungal Unknown 430 and
type I PKS/NRPS L. enzymogenes Cytotoxic 431
Alteromonas sp.
((Di)Bromo)- Hybrid FAS/NRPS Pseudoalteromonas sp. Antibacterial Unknown 523–525
alterochromides Antifungal
Prodigiosin Hybrid cis-AT (Pseudo)Alteromonas rubra Antibacterial DNA cleavage 508–512
PKS/NRPS/Other Serratia sp. Antifungal
Vibrio sp.
Hahella chejuensis
Streptomyces sp.
Cycloprodigiosin Hybrid PKS– (Pseudo)Alteromonas rubra Antibacterial F-ATPases 511 and
NRPS/other V. gazogenes Inhibition of protein 513
synthesis
Tambjamines Hybrid PKS/NRPS? P. tunicata Antibacterial DNA 526–528
Antifungal
Antitumor
Immunosuppressive
Thiomarinol A–G Hybrid trans-AT P. luteoviolacea Antibacterial Isoleucyl-tRNA 529–533
PKS/NRPS synthetase
Xenorhabdins 8–13 Hybrid FAS/NRPS P. luteoviolacea Antibacterial Unknown 534
Indolmycin Other P. luteoviolacea Antibacterial Tryptophan-tRNA 535–538
Streptomyces griseus synthetase
2,6-Dibromophenol Other P. luteoviolacea 2ta16 Antifungal Unknown 539
2,4-Dibromo-6- Other P. luteoviolacea Antibacterial Unknown 539 and
chlorophenol 540
Hexa-bromo-2,20 - Other P. luteoviolacea I-L-33 Antibacterial Unknown 541 and
bipyrrole 542
4-Hydroxybenzaldehyde Other P. luteoviolacea I-L-33 Antibacterial Unknown 542
p-Hydroxybenzoic acid Other P. avipulchra JG1 Antibacterial Unknown 543
trans-Cinnamic acid Other P. avipulchra JG1 Antibacterial Unknown 543
MC21-A Other Pseudoalteromonas sp. Antibacterial Unknown 544
Pentabromopseudilin Other Pseudoalteromonas sp. Antibacterial 545–547
Alteromonas sp. Antifungal
View Article Online
Table 1 (Contd. )
Cytotoxic Interference with

the synthesis of
macromolecules
n-Propyl-5- Other P. luteoviolacea I-L-33 Antibacterial Unknown 542
hydroxybenzoate
2,3,5,7- Other Pseudoalteromonas sp. Antibacterial Unknown 547
Tetrabromobenzo- Antifungal
furo[3,2-b]pyrrole
Tetrabromopyrrole Other Pseudoalteromonas sp. Antibacterial Unknown 542
Alteromonas sp. Antifungal
4,40 ,6-Tribromo-2,20 - Other P. phenolica D5047 Antibacterial Unknown 544 and
biphenol 547
40 -((3,4,5-Tribromo-1H- Other P. luteoviolacea I-L-33 Antibacterial Unknown 548
pyrrol-2-yl)methyl)
phenol
2,4,6-Tribromophenol Other P. luteoviolacea 2ta16 Antibacterial Unknown 539 and
Antifungal 540
Violacein Other Pseudoalteromonas sp. Antibacterial Unknown 549–553
Chromobacterium violaceum Antifungal
Alteromonas luteoviolacea Antiprotozoal
Collimonas sp. Antioxidant
Duganella sp. Antiviral
Escherichia coli Anti-ulcerogenic
Janthinobacterium sp. Antitumor
6-Bromoindolyl-3- Unknown P. avipulchra JG1 Antibacterial Unknown 543
acetic acid
Cyclo-(isoleucyl-prolyl- Unknown P. maricaloris Antibacterial Unknown 554
leucyl-alanyl) Antifungal
Isatin Unknown P. issachenkonni Antifungal Unknown 555–557
Korormicins Unknown Pseudoalteromonas sp. Antibacterial Na(+)-translocating 548, 558
NADH-quinone and 559
reductase
Norharman Unknown P. piscicida NJ6-3-1 Antibacterial Unknown 560 and
Antifungal 561
Ogipeptins Unknown Pseudoalteromonas Antibacterial LPS 562
sp. SANK 71903
Alteromonas
Alteramide A Hybrid iterative Alteromonas sp. Antifungal Unknown 430 and
type I PKS/NRPS P. piscicida 0T59 Cytotoxic 431
L. enzymogenes
Prodigiosin Hybrid cis-AT (Pseudo)Alteromonas rubra Antibacterial DNA cleavage 508–512
PKS/NRPS/other Serratia sp. Antifungal
Vibrio sp.
Hahella chejuensis
Streptomyces sp.
Cycloprodigiosin Hybrid PKS– (Pseudo)Alteromonas rubra Antibacterial F-ATPases 511 and
NRPS/other V. gazogenes Inhibition of protein 513
synthesis
2-n-Pentyl-4-quinolinol Other Alteromonas strain SWAT5 Antibacterial Unknown 129 and
Pseudomonas bromoutilis Algicidal 130
2-n-Heptyl-4-quinolinol Other Alteromonas strain SWAT5 Antibacterial Unknown 129 and
Pseudomonas aeruginosa 130
Pseudomonas bromoutilis
Pseudopyronines Other Alteromonas sp. KNS-16 Antibacterial Cell membrane 124–126
A and B Pseudomonas sp. Anti-parasitic FAS II (FabG/FabI/InhA)
Algicidal
Cytotoxic
Antifungal
Pentabromopseudilin Other Alteromonas sp. Antibacterial Interference with 545–547
Pseudoalteromonas sp. Antifungal the synthesis of
Cytotoxic macromolecules
Tetrabromopyrrole Other Alteromonas sp. Antibacterial Unknown 542
Pseudoalteromonas sp. Antifungal
View Article Online
Table 1 (Contd. )
Violacein Other Alteromonas luteoviolacea Antibacterial Unknown 549–552

Pseudoalteromonas sp. Antifungal
Chromobacterium violaceum Antiprotozoal

Collimonas sp. Antioxidant
Duganella sp. Antiviral
Escherichia coli Anti-ulcerogenic
Janthinobacterium sp. Antitumor
Serratia
Oocydin A trans-AT PKS Serratia sp. Antifungal Unknown 563–565
Dickeya sp. Anti-oomycete
Antitumor
Anti-hyperlipidemic
Serrawettin NRPS S. marcescens Antibacterial Cell membrane 566–568
W1/serratamolide Biosurfactant
Anticancer
Hemolytic
Serrawettin W2 NRPS Serratia sp. Antibacterial Unknown 569
Antifungal
Biosurfactant
Antitumor
Andrimid Hybrid type II Serratia sp. Antibacterial Acetyl-CoA carboxylase 92–96
PKS/NRPS Enterobacter cloacae
Vibrio coralliilyticus
Pantoea agglomerans
Zeamines Hybrid PUFA- Serratia plymuthica Antibacterial Cell membrane 570–574
synthase-like Dickeya zeae EC1 Antifungal
assembly line/cis-AT Phytotoxic
PKS/NRPS Cytotoxic
Prodigiosin Hybrid PKS/NRPS/other Serratia sp. Antibacterial DNA 508–512
Vibrio sp. Antifungal F-ATPases
(Pseudo)Alteromonas rubra Antiprotozoal Plasma membrane
Hahella chejuensis Antiviral
Streptomyces sp. Antitumor
Immunosuppressant
Bacteriocins L RiPP S. marcescens Antibacterial Unknown 575 and
and 28b 576
Serracin P RiPP S. plymuthica J7 Antibacterial Cell membrane 577
Serraticin A RiPP S. proteamaculans 136 Antibacterial Unknown 578
Pyrrolnitrin Other Serratia sp. Antibacterial Respiratory electron 118–122
Burkholderia sp.
Pantoea agglomerans
M. fulvus
Escherichia
Colicins A, B, E1, N, S4, RiPP Escherichia coli Antibacterial Cell membrane 579–584
K, 5–10, Ia, Ib, V and Y
Colicins E2, E7, E8 and RiPP E. coli Antibacterial DNA 585 and
E9 586
Colicins D and E5 RiPP E. coli Antibacterial tRNA 587 and
588
Colicins E3, E4 and E6 RiPP E. coli Antibacterial rRNA 589–591
Colicin M RiPP E. coli Antibacterial Peptidoglycan 592
Microcin C RiPP E. coli Antibacterial Aspartyl tRNA 593 and
synthetase 594
Microcin J25 RiPP E. coli Antibacterial RNA polymerase 595–597
Violacein Other Chromobacterium violaceum Antibacterial Unknown 549–552
Alteromonas luteoviolacea Antifungal
Collimonas sp. Antiprotozoal
Duganella sp. Antioxidant
Escherichia coli Antiviral
View Article Online
Table 1 (Contd. )
Janthinobacterium sp. Anti-ulcerogenic

Pseudoalteromonas sp. Antitumor
Chromobacterium
Iodinin Other Chromobacterium iodinum Antibacterial DNA, DNA-dependent 598–600
Brevibacterium iodinum Antifungal RNA synthesis
Streptosporangium sp. DSM Cytotoxic
45942
Acidithiobacillus
ferrooxidans
Lysobacter antibioticus
Pseudomonas sp.
Violacein Other Chromobacterium violaceum Antibacterial Unknown 549–552
Alteromonas luteoviolacea Antifungal
Collimonas sp. Antiprotozoal
Aerocyanidin Unknown C. violaceum ATCC53434 Antibacterial Unknown 601
Aerocavin Unknown C. violaceum ATCC53434 Antibacterial Unknown 602
3,6- Unknown C. violaceum Antibacterial Unknown 603
Dihydroxyindoxazine/Y-
T0678H
Pantoea
Andrimid Hybrid type II Pantoea agglomerans Antibacterial Acetyl-CoA carboxylase 92–96
PKS/trans-AT Enterobacter cloacae
PKS/NRPS P. uorescens
Serratia sp.
Pantocins A and B RiPP Pantoea sp. Antibacterial L-Histidinolphosphate 604–606
aminotransferase
D-Alanylgriseoluteic Other P. agglomerans Eh1087 Antibacterial Induction of SOS 516 and
acid Vibrio sp. SANK 73794 respons and redox 517
activity
Pyrrolnitrin Other P. agglomerans Antibacterial Respiratory electron 118–122
Serratia sp.
Burkholderia sp.
M. fulvus
Enterobacter
Andrimid Hybrid type II Enterobacter cloacae Antibacterial Acetyl-CoA carboxylase 92–96
PKS/trans-AT Pantoea agglomerans
PKS/NRPS P. uorescens
Serratia sp.
Enterocin AS-48 RiPP Enterobacter sp. Antibacterial Cell membrane 607
Cloacin DF13 RiPP E. cloacae Antibacterial rRNA 608 and
609
Dickeya
Oocydin A trans-AT PKS Dickeya sp. Antifungal Unknown 563–565
Serratia sp. Anti-oomycete
Antitumor
Anti-hyperlipidemic
Indigoidine NRPS Dickeya dadantii Antibacterial Unknown 80–87
Erwinia chrysanthemi Antifungal
Streptomyces sp.
Arthrobacter sp.
P. indigofera
View Article Online
Table 1 (Contd. )
Phaeobacter sp. Y4I

Leisingera sp. JC1
Zeamines Hybrid PUFA- Dickeya zeae EC1 Antibacterial Cell membrane 570–574
synthase-like Serratia plymuthica Antifungal
assembly line/cis- Phytotoxic
AT PKS/NRPS Cytotoxic
Pectobacterium
Carocin S1 RiPP Pectobacterium carotovorum Antibacterial DNA 610
Carocin S2 RiPP P. carotovorum Antibacterial tRNA 611
1-Carbapen-2-em-3- Other P. carotovorum Antibacterial Peptidoglycan 612–616
carboxylic acid Erwinia sp. transpeptidases
Serratia sp.
TTO1
Erwinia
Indigoidine NRPS Erwinia chrysanthemi Antibacterial Unknown 80–87
Dickeya dadantii Antifungal
Streptomyces sp.
Arthrobacter sp.
Pseudomonas indigofera
Phaeobacter sp. Y4I
Leisingera sp. JC1
1-Carbapen-2-em- Other Erwinia sp. Antibacterial Peptidoglycan 612–616
3-carboxylic acid Serratia sp. transpeptidases
TTO1
Pectobacterium carotovorum
Klebsiella
Klebicins A and B RiPP Klebsiella sp. Antibacterial DNA 617 and
618
Klebicin C RiPP Klebsiella sp. Antibacterial rRNA 619
Klebicin D RiPP Klebsiella sp. Antibacterial tRNA 619
Yersinia
Holomycin NRPS Y. ruckeri Antibacterial RNA polymerase 532 and
Streptomyces sp. 620
Pesticin RiPP Y. pestis Antibacterial Peptidoglycan 621
Enterocoliticin RiPP Y. enterocolitica 29930 Antibacterial Cell membrane 622 and
623
Ralstonia
Micacocidin Hybrid iterative Ralstonia solanacearum Antibacterial Unknown 90 and 91
type I PKS/trans-AT GMI1000
PKS/NRPS Pseudomonas sp. no. 57-250 Antifungal
Ralfuranone I NRPS R. solanacearum Antibacterial Unknown 624 and
Antifungal 625
Chitinophaga
Elansolid A trans-AT PKS Chitinophaga sancti Antibacterial Unknown 626 and
Cytotoxic 627
Pinensins RiPP Chitinophaga pinensis Antifungal Unknown 628
Janthinobacterium
Jagaricin NRPS Janthinobacterium Antifungal Unknown 629
Agaricidamnosum Anti-proliferative
View Article Online
Table 1 (Contd. )
Cytotoxic
Janthinocin A–C NRPS Janthinobacterium lividum Antibacterial Unknown 630
Collimonas
Tripropeptins NRPS Collimonas fungivorans Antibacterial Undecaprenyl 416
Lysobacter sp. pyrophosphate
Violacein Other Collimonas sp. Antibacterial Unknown 549–552
Chromobacterium violaceum Antifungal
Alteromonas luteoviolacea Antiprotozoal
Empedobacter
Empedopeptin NRPS Empedobacter haloabium Antibacterial Lipid II 631 and
ATCC 31962 632
Lactivicin Unknown Empedobacter lactamgenus Antibacterial Penicillin-binding 440–442
YK-258 proteins
L. albus YK-422
Flexibacter
Formadicins Unknown Flexibacter Antibacterial Penicillin-binding 633 and
alginoliquefaciens proteins 634
YK-49
TAN-1057 A-D Unknown Flexibacter sp. Antibacterial Peptidoglycan 635
elongation
Xanthomonas
Albicidin Hybrid PKS–NRPS X. albilineans Antibacterial DNA gyrase A 636 and
Phytotoxic 637
Glycinecin A RiPP X. campestris Antibacterial Cell membrane 638 and
639
Phaeobacter
Tropodithietic acid Other Phaeobacter inhibens Antibacterial Proton motive force 640–642
Antitumor (dissipation by proton
antiport mechanism)
Roseobacticides Other P. inhibens Algicidal Unknown 643 and
644
Candidatus Entotheonella palauensis

Theopalauamide Unknown Candidatus Entotheonella Antifungal Ergosterol 645
palauensis
Theonegramide Unknown Candidatus Entotheonella Antifungal Unknown 646
palauensis
Other
Tartrolon D and E trans-AT PKS Teredinibacter turnerae Antibacterial Cell membrane 647
T7901
Lysobactin/katanosin B NRPS Cytophaga strain PBJ-5356 Antibacterial Lipid II 418–421
Lysobacter sp.
Teixobactin NRPS Eleheria terrae Antibacterial Lipid II 648 and
649
Ecteinascidin ET-743 NRPS Candidatus Antibacterial DNA 650 and
Endoecteinascidia Antitumor 651
frumentensis
Kalimantacin A/ Hybrid trans-AT Alcaligenes sp. YL-02632S Antibacterial FabI 99–101
batumin PKS–NRPS Pseudomonas sp.
Ariakemicins A and B Hybrid PKS–NRPS Rapidithrix sp. Antibacterial Unknown 652
Enacyloxin IIa Hybrid cis-/trans-AT Frateuria sp. W-315 Antibacterial Elongation factor tu 455–457
PKS/NRPS Burkholderia sp.
Colicin U RiPP Shigella boydii Antibacterial Cell membrane 653
View Article Online
Table 1 (Contd. )
Indothiazinone Other Ohtaekwangia kribbensis Antifungal Unknown 654

706 Cytotoxic
Pelagiomicin Other Microbulbifer variabilis Antibacterial Unknown 515

C/glycylgriseoluteic Vibrio sp. Antitumor
acid
Thiotropocin Other Roseobacter strain 27-4 Antibacterial Unknown 138–141
Pseudomonas sp. CB-104 Antifungal
Antiprotozoal
EM5400 monobactams Unknown Agrobacterium radiobacter Antibacterial Penicillin-binding 655 and
SC 11742 proteins 656
Cyclo (L-Pro-L-Tyr) Unknown Aristabacter necator 679-2 Antibacterial Unknown 147–151
Pseudomonas sp. Antifungal
L. capsici AZ78 Anti-oomycete
Xanthobaccins Unknown Stenotrophomonas sp. Antifungal Mycelial growth 438 and
strain SB-K88 inhibition and 439
Lysobacter sp. SB-K88 Anti-oomycete zoospore lysis
Trisindoline Unknown Rubrivivax benzoatilyticus Antibacterial Unknown 522
JA2
V. parahaemolyticus Bio249 Cytotoxic
Isatis costata
Cyclo(D-Leu-D-Arg), Unknown Achromobacter Antibacterial Unknown 657
cyclo(L-Trp-L-Arg)
and cyclo(D-Trp-D-Arg)
Vibrindole A Unknown Symbiobacterium Antibacterial Unknown 519
thermophilum IAM14863
V. parahaemolyticus Antifungal
Streptomyces sp. Antitumor
9 J. Herrmann, A. A. Fayad and R. Müller, Nat. Prod. Rep.,

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Volume 34 Number 7 July 2017 Pages 679–934

Themed issue: Novel Antibiotics and Antimicrobial Resistance

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Antibiotics from Gram-negative bacteria:

1. Introduction 7. Conclusions and perspectives

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Matthew Jenner obtained a BSc Greg Challis is the Monash

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Fig. 1 Taxonomic overview of Gram-negative genera known to produce antimicrobial metabolites.

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Fig. 2 Examples of antimicrobial polyketides produced by Gram-negative bacteria.

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3.1 Teixobactin lipid II and lipid III, respectively.649,736 Resistance to teixobactin

whelming majority of microbial species in nature remain

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bacterium Chromobacterium violaceum.780

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organobromine compounds and have an impressive enzymatic

acid composition of the cyclic peptide, the length of the

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Fig. 20 Examples of antimicrobial RIPPs produced by Gram-negative bacteria.

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Fig. 23 Examples of other antimicrobial metabolites from Gram-negative bacteria.

6. Other 2011.123 Recent synthetic studies have elucidated the absolute

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Table 1 Comprehensive overview of antimicrobial metabolites known to be produced by Gram-negative bacteria

Compound Biosynthetic origin Producer(s) Bioactivity Molecular target Ref.

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Compound Biosynthetic origin Producer(s) Bioactivity Molecular target Ref.

Tolaasin I NRPS P. tolaasii Antibacterial Cell membrane 71–74