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Opportunities for natural products in 21st century

antibiotic discovery
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Cite this: Nat. Prod. Rep., 2017, 34, 694

Gerard D. Wright

Received 17th March 2017
DOI: 10.1039/c7np00019g
rsc.li/npr
Natural products and their derivatives are mainstays of our antibiotic drugs, but they are increasingly in peril.
The combination of widespread multidrug resistance in once susceptible bacterial pathogens,
disenchantment with natural products as sources of new drugs, lack of success using synthetic
compounds and target-based discovery methods, along with shifting economic and regulatory issues,
conspire to move investment in research and development away from the antibiotics arena. The result is
a growing crisis in antibiotic drug discovery that threatens modern medicine. 21st century natural
product research is perfectly positioned to fill the antibiotic discovery gap and bring new drug
candidates to the clinic. Innovations in genomics and techniques to explore new sources of
antimicrobial chemical matter are revealing new chemistry. Increasing appreciation of the value of
narrow-spectrum drugs and re-examination of once discarded chemical scaffolds coupled with
synthetic biology methods to generate new compounds and improve yields offer new strategies to
revitalize once moribund natural product programs. The increasing awareness that the combination of
antibiotics with adjuvants, non-antibiotic compounds that overcome resistance and enhance drug
activity, can rescue older chemical scaffolds, and concepts such as blocking pathogen virulence present
orthogonal strategies to traditional antibiotics. In all these areas, natural products offer chemical matter,
shaped by natural selection, that is privileged in this therapeutic area. Natural product research is poised
to regain prominence in delivering new drugs to solve the antibiotic crisis.

medical procedures including immune-depleting cancer

1. The antibiotics crisis
Microbially-derived natural products occupy a storied place in
antibiotic drug discovery and development. The rst wave of
antibiotics that emerging before the 1940s consisted of
synthetic compounds such as the arsenical salvarsan and the
sulfonamides. However, the bulk of the antimicrobials that
form the basis of our current antibiotic drug arsenal arose from
studies of the secondary metabolites produced by microbes.
Fleming’s discovery in 1928 of the bactericidal activity of the
fungal metabolite penicillin, followed by Dubos’s exploration of
antimicrobial peptides produced by bacilli and augmented by
Waksman’s mining of the compounds produced by soil acti-
nomycetes, ushered in the Golden Age of antibiotic discovery.1
The turning point in this history was the development of
penicillin into a ‘miracle drug’ during the Second World War.
The next three decades witnessed the discovery of the majority
of antibiotic scaffolds that are in clinical use today.
These natural product antibiotics irrevocably changed
medicine. Feared infections that plagued humanity for
millennia were now controllable diseases. Once unthinkable
M.G. DeGroote Institute for Infectious Disease Research, Department of Biochemistry
and Biomedical Sciences, DeGroote School of Medicine, McMaster University, 1280
Main Street West, Hamilton, ON L8N 4K1, Canada. E-mail: wrightge@mcmaster.ca
chemotherapy, organ transplantation, heart surgery, and the
replacement of skeletal joints, are now commonplace because
of the infection control provided by antibiotics. It is fair to say
that together with anesthetics that control pain and enable
radical surgical interventions, antibiotics are the foundation
drugs of modern medicine, forever changing what we expect
from medical practice. Antibiotics have a massive impact on
both health and society. Yet we are in increasing danger of
losing them.
In his Nobel address in 1945, Fleming warned of the
potential for the emergence of bacterial resistance to under-
mine the efficacy of the newly discovered penicillin.2 Now, 70
years later, Fleming’s warning proved prescient: once manage-
able infections are increasingly difficult to control due to the
emergence of resistance. In a phenomenon not predicted by
Fleming, we now know that bacteria can collect many genetic
elements that confer high-level resistance to several antibiotics
resulting in multidrug resistance (MDR) phenotypes.3 Para-
doxically, despite a growing clinical need, the pharmaceutical
industry, which was once at the forefront of infectious disease
research and development, has largely abandoned antibiotics.
Instead, efforts are channeled towards more tractable chronic
diseases that have more favorable prospects for a return on
investment, for example diabetes and cardiovascular disease.

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The result is a growing innovation gap that, if unsolved, will
return us to the pre-antibiotic era where the fruits of modern
medicine are out of reach for many. Indeed, as seen by recent
events where patients succumb to once treatable pathogens that
are now resistant to all available antibiotics, we are already in
a grave situation.4–6
In many ways, the remarkable success of natural product
antibiotics has contributed to the current problem. First, while
it is certain that MDR pathogens are on the rise all across the
globe, in particular in hospitals and other health care facilities,
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our legacy antibiotics oen remain quite useful. This is espe-
cially true for community-acquired infections, though MDR is
on the rise here as well. These old drugs are cheap and non-
toxic. This is good for patients, health care providers, and
funders. That said, complacent reliance on these drugs fails to
anticipate the inevitable – that they are vulnerable to resistance
and that we need replacements and new ways of dealing with
infection.
Second, the efficacy and safety of our legacy antibiotics
provide demanding benchmarks to be met. Antibiotics are
frequently given on the gram scale, orders of magnitude higher
than other drugs. Toxicity vs. efficacy ratios are consequently
tough to match for new compounds. This also brings into
question the difficulty of clinical trials for new antibiotics.7
Placebo-controlled trials are unethical in the antibiotic realm
where we know that withholding a drug can lead to death.
Instead, antibiotics are measured against a best available
comparator. If the new drug is designed to overcome resistance,
yet the population of resistant bacteria causing disease in the
trial is low, statistical efficacy may not be met. Furthermore,
a drug that is designed for resistant bacteria, but yet has some
manageable host toxicity, may never see sufficient patients in
a trial (oen conducted at large Western hospitals) and the
therapeutic index may never be adequately addressed. A mildly
Dr Gerard (Gerry) Wright is the
Michael G DeGroote Chair in
antiinfective research and the
director of the Michael G.
DeGroote Institute for Infectious
Disease Research at McMaster
University in Hamilton, Ontario.
As an undergraduate student, he
worked on the biosynthesis of the
siderophore aerobactin. He
received his PhD in Chemistry at
the University of Waterloo
working on fungal P-450 enzymes
as targets for antifungal drugs. He was a postdoctoral fellow with
Christopher Walsh at Harvard Medical School (1991–1992) where
he worked on the molecular mechanism of the newly emerging
resistance to vancomycin in enterococci. In 1993 he joined the
Department of Biochemistry at McMaster University where for over
two decades he has explored the mechanisms of resistance and
biosynthesis of a large number of antibiotics with the support and
collaboration of a merry gang of creative and dedicated colleagues.
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toxic antibiotic that can be used to treat severe MDR infections
may never be approved or invested in because of the historical
efficacy and safety margin of drugs like penicillin. These issues
bring to the fore the difficulty that clinicians face in that, for the
most part, the causative agent of the infection is not known. The
lack of molecular diagnostics that accurately and rapidly iden-
tify the pathogen to guide clinicians and clinical trials is a major
confounding problem. Addressing the antibiotics crisis will
take a concerted effort across many aspects of society and areas
of research.8 Natural products must continue to play a funda-
mental role in solving this global problem.
2. The impact of natural products in
antibiotic discovery
Natural products of microbial origin are privileged in the sphere
of antibiotic development. The sulfa drugs, trimethoprim, u-
oroquinolones, and oxazolidinones (Fig. 1) are examples of
highly successful synthetic compounds in clinical antibiotic use
and provide proof that these should not be abandoned in our
search for 21st century antibiotics. Nevertheless, the majority of
antibiotic drugs are derived from microbial natural products.
Decades of activity-guided purication of antibiotics from
microbial sources has identied an estimated 28 000
compounds, approx. 200 of which have found direct use as
drugs (Fig. 2).9
Improvements by semi-synthesis on these scaffolds gener-
ated another 200–300 drugs, greatly exceeding the number of
synthetic antibiotics in clinical use (Fig. 3).
2.1. Why are natural product antibiotics privileged in this
therapeutic space?
These compounds are the products of millions of years of
evolution. They are fashioned by natural selection to interact
with cellular targets with high efficiency and selectivity and to
avoid resistance. Furthermore, as products of evolution, they
intrinsically possess the physiochemical properties necessary
for penetrating bacterial cells, unlike many synthetic mole-
cules.10,11 Molecular selectivity is a hallmark of many natural
product antibiotics, with relatively few broadly toxic
compounds, and those which are, such as the enediynes, have
a tightly regulated biosynthesis and are molecularly neutralized
through co-expression of protective proteins.12
2.2. If natural products are so successful as antibiotics, why
can’t we easily identify new ones?
Most natural product antibiotics were detected using ‘The
Waksman Platform’.13 In this strategy, natural product extracts,
principally derived from bacteria and fungi, are screened for
bacterial cell killing effects in the laboratory using simple
culture-based assays. This approach powered the Golden Age of
antibiotic discovery resulting in our current highly successful
drugs. Because of the difficulty in the clinic of accurately iden-
tify the disease-causing pathogen and the efficacy and safety
index of the rst successful natural product drugs, the criteria
governing antibiotic discovery was strict. Candidate antibiotics
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The past – our legacy synthetic antibiotics. These scaffolds span the Golden Age of antibiotics with the sulfonamides such as sulfa-
Fig. 1
methoxazole discovered in the 1930s, and the oxazolidinone linezolid in the 1980s.
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had to show broad-spectrum efficacy and the absence of human

toxicity. Compounds with narrow-spectrum activity, e.g. to one
genus or species, those with any toxic effects, or potential
pharmacological liabilities were discarded early in the discovery
process, oen never to be further studied.
Furthermore, most discovery efforts in the Golden Age
focused on mining the compounds produced by bacteria of the
order Actinomycetales, commonly derived from the soil. This
emphasis on broad-spectrum compounds from a single order of
bacteria eventually resulted in the frequent re-isolation of the
same compounds that are produced by many species and
genera. Removing producers of such compounds early in drug
discovery, a process termed dereplication, became a priority but
was resource consuming. The growing realization that new Fig. 3 The past – our legacy semi-synthetic antibiotics. These are the
antibiotic discovery from this traditional source resulted in result of successful semi-synthetic derivatives of natural products
diminishing returns caused a pivot away from natural products (changes shown in blue) improved efficacy, safety and expanded
towards synthetic compounds. This occurred at a historic point, spectrum.
the 1980s and early 1990s, when large-scale combinatorial
synthesis and genome-inuenced target-based drug discovery
emerged on the scene; subsequently, natural product divisions 3. Prospects for natural products in
in many pharmaceutical companies were scaled back or shut-
tered. Ironically, this occurred at a time when the genomics,
21st century antibiotic discovery
molecular biology, and biochemistry of natural products To address the antibiotics crisis, we must tackle the problem
became increasingly tractable and popular in academic using several parallel approaches. First, we need to identify new
research programs, revealing a wealth of opportunity for new antibiotic chemical scaffolds that evade the resistance mecha-
discovery strategies beyond the traditional Waksman Platform. nisms circulating in pathogens today. Second, we need to
preserve as best we can our existing drugs. Finally, we need to

Fig. 2 The past – our legacy natural product antibiotics. These drugs were discovered using the Waksman Platform,13 where microbial extracts
were screened in whole cell killing assays.

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explore non-traditional anti-infective strategies. Natural prod-
ucts can contribute to all these areas.14
3.1. New antibiotics
The Actinomycetales are the source of the majority of our
current antibiotic drugs. While the Waksman Platform
frequently re-identies known compounds from extracts of
these bacteria, these can be readily identied.15 Genome
sequencing reveals that each strain can produce 20–40
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new antimicrobial chemistry. Ironically, despite the success of
b-lactams, which account for 60% of antibiotics in clinical
use, fungal sources of antibiotics have not been as extensively
pursued (the exception is fusidic acid, a topical antibiotic),
though, like actinomycetes, genome sequencing identies
dozens of natural product biosynthetic clusters per fungal
genome.19
It is well accepted that our capacity to grow most bacterial
species in the lab is quite limited. We are therefore missing
a signicant number of microbial genomes using the standard

secondary metabolites, many of which have not yet been char-

Waksman Platform approach, raising the question of what
acterized and some no doubt have antibiotic activity. Most of
chemical diversity we are failing to sample as a result. Lewis and
these are not readily produced under laboratory settings and are
Epstein’s laboratory have pioneered efforts such as the iChip to
therefore not tested in traditional assays of extracts. Efforts to
tame unculturable bacteria for growth in the lab that enables
awaken these so-called ‘cryptic’ or ‘silent’ biosynthetic gene
the mining of antibiotic ‘dark matter’.20 Importantly, with the
clusters have been pursued including altering the growth
isolation of teixobactin (Fig. 6), a new antibiotic scaffold, they
conditions, the overexpression of genetic regulators, the addi-
have demonstrated that such efforts can yield unique chem-
tion of chemical elicitors, and the capture of biosynthetic gene
istry.21 Another method is to forego cell culture and capture
clusters for expression in heterologous hosts. These efforts have
biosynthetic gene clusters from total metagenomic DNA. Using
resulted in several rare and new compounds being identied
such an approach, Brady and co-workers have identied several
(e.g. refs 16–18) (Fig. 4) offering encouragement that such
new antibiotic compounds including tetarimycin A (Fig. 6).22,23
strategies, especially if performed in high throughput as is
These strategies demonstrate concretely that the der-
occurring in companies such as Warp Drive Bio, can produce
eplication barrier can be overcome, and that new antibiotic
new antibiotic scaffolds.
scaffolds can be found in microbes. Plant-derived compounds
An alternative to deep mining of Actinomycetales genomes is
tend to be less selective and less sufficiently potent, conse-
the exploration of genera that have not been as extensively
quently making them less desirable as conventional antibiotic
explored for antibiotics in the past but, nevertheless, are known
drugs.
to produce antibiotic substances. These include proteobacteria
Furthermore, altering the screening strategies from the
such as myxobacteria, pseudomonads, burkholderias, among
traditional Waksman approach to include for example nutrient-
other Gram negative bacteria (Fig. 5). Firmicutes such as bacilli
limiting conditions,24 stress,25 target depletion to sensitize
were among the rst bacteria to be shown to produce antibi-
strains,26–28 genetic and chemical synthetic lethality29–32 and
otics, some such as gramicidin are still in use as topical agents
today, and these also are worthy of systematic exploration for

Fig. 4The present – antibiotics from cryptic biosynthetic gene clusters. Awakening of ‘cryptic’ or ‘silent’ biosynthetic clusters that are found in all
sequenced actinomycetes offers a route to new chemical matter. Examples shown here are taromycin,18 N-acetylmureidomycin,17 and
pulvomycin.16

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Fig. 5 The present – antibiotics from Gram negative bacteria. Mupirocin is a successful anti-staphylococcal topical antibiotic in clinical use while
the other examples, enacyloxin IIa, myxopyronin and pantocin A have yet to be introduced into the clinic.

screens in whole organisms such as Caenorhabditis elegans33
offers new opportunities to identify antibiotic leads.34
3.2. ‘Old’ antibiotics
Of the 28 000 natural product antibiotics discovered over the
past decades, >0.1% are in clinical use. Many of the other 99.9%
will never be suitable as drugs because of the intractable issues
of efficacy, toxicity, stability, etc. Nevertheless, some of these
compounds no doubt are worthy of reinvestigation. The
example of daptomycin, once discarded for issues of toxicity
and narrow spectrum but now a highly protable drug proves
the point.35 A major challenge to pursuing this hypothesis is
that there is no effective way to revisit these compounds in
a systematic fashion. Most are unavailable for purchase, and the
historical libraries of pharmaceutical companies are not readily
available. An international effort to generate and distribute
a library of microbially-derived natural products could have
a signicant impact on antibiotic discovery. The efforts of CO-
ADD (the Community for Open Antimicrobial Drug Discovery),
which seeks to mine synthetic and natural product chemicals
generated by labs across the globe is a potential opportunity
here.36
Variations of known antibiotic scaffolds also have value.
Even small chemical changes can result in substantial effects on
efficacy and drug-like properties. Access to many scaffold vari-
ations provides valuable starting material for expanding the
chemical space around natural product antibiotics that can be
further elaborated by semi-synthesis. Using resistance as an
initial screen is an easy way to enrich strain collection
surrounding distinct chemical scaffolds37 and to predict
potential resistance mechanisms that may emerge in the
clinic.38
3.3. Rescuing legacy antibiotics
An orthogonal strategy to new antibiotic discovery is the iden-
tication of compounds that lack antibiotic activity but which
enhance the activity of our existing antibiotics. Such antibiotic
adjuvants39 can improve the efficacy of legacy antibiotics and
decrease the frequency of resistance, thereby preserving drugs
that are safe and well known to clinicians. Adjuvants are clas-
sied into two types, those that act on bacteria directly (Type I),
and those that enhance host antimicrobial properties (Type II).
Type I adjuvants include inhibitors of acquired resistance (Type
Ia), and examples include inhibitors of b-lactamases that are in

Fig. 6 The present – antibiotics from microbial ‘dark matter’. Microbial genomes of rare, e.g. teixobactin from Eleftheria terrae,21 or uncultured
(metagenomes), e.g. tetarimycin A,23 offer routes to access new antibiotic chemical matter.

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clinical use today; Type Ib compounds overcome intrinsic
resistance mechanisms such as antibiotic entry and efflux.
Natural products offer great opportunities here as well. The
rst inhibitor of a b-lactamase, clavulanic acid (Fig. 7), was
isolated from a b-lactam antibiotic producer, Streptomyces
clavuligerus. It seems reasonable that, in addition to being
sources of antibiotics, microbes are also sources of inhibitors of
resistance. Our recent isolations of an inhibitor of metallo-b-
lactamases, aspergillomarasmine A, from a fungus40 and of
rifamycin efflux, A301A, from a bacterium41 are consistent with
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this hypothesis (Fig. 7). In the antibiotic adjuvant realm there is
certainly opportunity for plant natural products, and indeed
molecules such as berberine have already been shown to be
inhibitors of efflux for example.42 Natural products also can
contribute to the discovery of Type II adjuvants as we have
shown with the macrophage-enhancing streptazolin (Fig. 7).43
3.4. Alternatives to antibiotics
The unparalleled efficacy and potency of antibiotics have
resulted in the primacy of such compounds to control infection
for over seven decades. Alternatives such as antivirulence
compounds or biolm inhibitors have therefore not been put
into clinical practice, despite being touted in academic circles.
One of the principal barriers to the success of such strategies in
the drug-discovery eld is the design of suitable clinical trials
for efficacy and for disease prevention in the case of
Fig. 7 The future – antibiotic adjuvants. Antibiotic adjuvants are non-
antibiotic compounds that enhance the cell killing activities of anti-
biotics by blocking resistance or enhancing host defenses.
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antivirulence. Consequently, combinations with antibiotics
may offer the most logical way forward for many antibiotic
alternatives in the short- to medium-term. Compelling targets
include blocking the activities of bacterial toxins, secretion
systems, adhesins, impairing the acquisition of vital nutrients,
and other molecular requirements for infection or biolm
formation. Microbial natural products such as balomycin A1
and brefeldin A (Fig. 8) block vesicle trafficking in eukaryotic
cells and therefore have been identied as antivirulence
factors.44 But plants are rich in compounds with antivirulence
properties including hamamelitannin, which blocks Staphylo-
coccus aureus quorum sensing and sensitizes biolms to anti-
biotics,45 phloretin which inhibits Clostridium difficile toxins,46
and avones and sapogenins that impede virulence in MRSA47
(Fig. 8). There is great opportunity here for identifying
compounds and mixtures from both plants and microbes that
attenuate microbial pathogenesis, and which can contribute to
21st century anti-infective medicines.
3.5. Diversity through synthetic biology
Natural product biochemistry, molecular biology, and genomics
are now sufficiently advanced to allow the rational exploitation
of compound production in more directed studies with the aim
of expanding chemical diversity. The rst efforts in this area,
pioneered almost 20 years ago,48 foresaw the opportunity but
were outside the skill sets and resources of most laboratories.
The dropping costs of genome and metagenome sequencing,
coupled with advances in the increasingly accurate prediction
Fig. 8 The future – antivirulence compounds. These compounds
diminish the ability of pathogens to cause infection, but do not actually
kill the cells. These offer the ability to control infection before it starts.
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of natural product structures from biosynthetic genes,49–52 are
enabling the mining of heretofore rare or impossible-to-study
natural product biosynthesis. The advent of improved cluster
capture methods53,54 together with optimized strategies for
hosts of heterologous gene expression55,56 and the ability to
refactor entire genes, regulatory elements, and even clusters as
a result of the low-cost of gene synthesis18 is enabling the
movement of the eld rmly into the area of synthetic biology.57
This is an area where traditional natural product collection,
chemistry, semi-synthesis, new cultivation strategies, and strain
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improvement can synergize to generate increased chemical
diversity around scaffolds that can nd use in discovery efforts
in the antibiotics eld.
4. Conclusions
The challenge of the antibiotics crisis needs to be met with
concerted efforts across many disciplines and areas of expertise.
Natural products led the way during the Golden Age of antibi-
otic discovery and, despite a lull of about 30 years, there is
considerable reason to believe that natural products still have
much to offer. Our ability to mine, extract, produce, charac-
terize, and manipulate natural products has never been greater.
The existing chemical diversity that has yet to be effectively
explored in the antibiotic realm is staggeringly large. Further-
more, these compounds are privileged starting points in the
antimicrobial eld that can now be enhanced using synthetic
biology strategies. There is much to be excited about and
encouraged by. Whereas it is important to not be a Pollyanna,
since the barriers to moving new discoveries out of the lab and
into the clinic are fraught with peril and compounds can fail for
many reasons, the eld of natural products is well positioned to
once again lead in innovation for solving the antibiotic crisis in
the Resistance Era.
5. Acknowledgements
I am grateful for funding from the Canadian Institutes of Health
Research, the Natural Sciences and Engineering Research
Council, and by a Canada Research Chair in Antibiotic
Biochemistry.
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