Biochemical Pharmacology 133 (2017) 63–73

Contents lists available at ScienceDirect

Biochemical Pharmacology
journal homepage: www.elsevier.com/locate/biochempharm

Review

What is an ‘‘ideal” antibiotic? Discovery challenges and path forward

Sheo B. Singh a,⇑, Katherine Young b, Lynn L. Silver c
a
SBS Pharma Consulting, Edison, NJ 08820, USA
b
MRL, Merck & Co., Inc., Kenilworth, NJ 07033, USA
c
LL Silver Consulting, Springfield, NJ 07081, USA

a r t i c l e i n f o a b s t r a c t

Article history: An ideal antibiotic is an antibacterial agent that kills or inhibits the growth of all harmful bacteria in a
Received 28 September 2016 host, regardless of site of infection without affecting beneficial gut microbes (gut flora) or causing undue
Accepted 9 January 2017 toxicity to the host. Sadly, no such antibiotics exist. What exist are many effective Gram-positive antibac-
Available online 10 January 2017
terial agents as well as broad-spectrum agents that provide treatment of certain Gram-negative bacteria
but not holistic treatment of all bacteria. However effectiveness of all antibacterial agents is being rapidly
Keywords: eroded due to resistance. This viewpoint provides an overview of today’s antibiotics, challenges and
Antibiotics
potential path forward of discovery and development of new (ideal) antibiotics.
ESKAPE
Antibacterials
Ó 2017 Elsevier Inc. All rights reserved.
Discovery challenges
Path-forward of discovery

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63
2. Brief review of key antibiotic classes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64
2.1. b-Lactam antibiotics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64
2.2. Glycopeptides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66
2.3. Lipopeptide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67
2.4. Aminoglycosides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68
2.5. Tetracyclines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68
2.6. Macrolides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69
2.7. Oxazolidinones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69
2.8. Quinolones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69
3. Challenges for discovery of an ideal new antibiotic without cross-resistance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69
3.1. Finding new chemical matter for an antibiotic lead . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69
3.2. The problem of entry into and retention of antibacterial chemicals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70
4. Multi target vs single target . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71
5. Broad-spectrum vs narrow spectrum . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71
6. New target-lead pair and new lead-old target pair . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71
7. Potential path forward for a new ideal antibiotic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72

1. Introduction Indeed, it has been estimated that the widespread availability of

Antibiotics are essential life-saving drugs that revolutionized
medicine, starting with the discovery of penicillin in 1928 [1].
⇑ Corresponding author.
E-mail addresses: sbs@sbspharma.com, sbsingh101@gmail.com (S.B. Singh).
antibiotics has added 30 years to human life expectancy in devel-
oped countries [2]. Since the discovery of penicillin, a number of
highly effective antibiotics have been discovered and developed
for clinical use in the treatment of bacterial infections [1,3]. Many
of these antibiotics have a broad-spectrum of activity, being effec-
tive in treatment of infections caused by Gram-positive as well as

http://dx.doi.org/10.1016/j.bcp.2017.01.003
0006-2952/Ó 2017 Elsevier Inc. All rights reserved.
64 S.B. Singh et al. / Biochemical Pharmacology 133 (2017) 63–73
Gram-negative bacteria, while others are effective for treatment of
infections caused by only Gram-positive bacteria. Ever since the
discovery of these drugs the question has been asked, ‘‘What is
an ideal antibiotic?” While specific circumstances may vary, philo-
sophically, an ideal antibiotic is an antibacterial agent that kills or
inhibits the growth of harmful bacteria in a host regardless of site
of infection without affecting beneficial microbes (gut/skin flora)
or causing undue toxicity to the host with low potential for resis-
tance. To accomplish this goal the agent has to demonstrate broad-
spectrum killing of Gram-positive as well as Gram-negative bacte-
ria; and it has to have exceptional blood/fluid circulation as well as
absorption, distribution, metabolism and excretion (ADME) prop-
erties allowing a low dose with a large therapeutic window. As
almost anything will cause toxicity at a high dose, the therapeutic
window is the only real measure to evaluate risk–benefit ratio. The
larger the therapeutic window, the better benefit a drug can pro-
vide without undue risk to the host.
No such ideal antibiotic exists or ever existed. Most antibiotics
in clinical use today do not have a broad-enough spectrum to treat
infections caused by all Gram-positive and Gram-negative bacte-
rial infections [4]. Therefore, most of the antibiotics today are
grouped as Gram-positive agents, Gram-negative agents, and a
few others with partial coverage of some Gram-positive as well
as some Gram-negative bacterial infections With a few exceptions,
all Gram-negative agents have activity against Gram-positive
pathogens albeit with differing potencies. The selection of antibi-
otics for the treatment of bacterial infections is still empirical but
is generally based on the physical symptoms presented by patients
and for which a given antibiotic is approved [5]. Such therapy is
started before results of a diagnostic test performed to determine
which bacterial strains are responsible for the infection are avail-
able [5]. Many of the oral Gram-negative antibiotics also inhibit
anaerobic pathogens in the gut altering gut flora, and leading to
diseases due to imbalance of gut microbial species.
In any case, an antibiotic, ideal or not, would not remain an
effective antibiotic forever due to the inevitable development of
resistance. Antibiotics, unlike non-infectious disease drugs, have
a relatively short useful lifespan due to acquired resistance [6].
So a specific ideal antibiotic will always be transitory and will have
to be replaced by newer ones when older ones become ineffective.
Drug discovery teams almost always want to develop an ideal
antibiotic but invariably hit a variety of roadblocks, mostly scien-
tific, which they cannot overcome, resulting in development of
imperfect but generally safe antibiotic.
Bacterial resistance to antibiotics is inevitable [6,7]. Bacteria
display various modes of resistance [8]. Resistance mechanisms
can include modification of the target to alter drug-binding, pro-
duction of alternate mechanisms to perform the function of the
target, inactivation of the drug, reduction of drug entry and expres-
sion of efflux pumps to eliminate drugs from inside bacterial cells
[8]. In certain cases bacteria are not only resistant to one class of
antibiotics but to several classes simultaneously, significantly
limiting treatment options. For example, methicillin-resistant
Staphylococcus aureus (MRSA) is not only resistant to penicillins
but also to cephalosporins and carbapenems [8]. However, MRSA
is generally susceptible to several Gram-positive drugs with
different modes of action (e.g., vancomycin, linezolid, daptomycin).
Nevertheless death rates from invasive MRSA infection remain
high [9]. These Gram-positive agents do not work in all cases for
variety of reasons, including failure to reach the site of bacterial
infection, poor tissue penetration, inactivation by body fluids,
incorrect diagnosis and treatment or some other reason?
What is more alarming currently is the rate of resistance to
many drugs occurring in many critical Gram-negative pathogens.
This has led to selection of a list of six priority pathogens
(two Gram-positive and four Gram-negative) termed ESKAPE
(Enterococcus faecium, S. aureus, Klebsiella pneumoniae, Acinetobac-
ter baumannii, Pseudomonas aeruginosa, and Enterobacter species)
by the Infectious Disease Society of America (IDSA) that need rapid
development of new antibiotics [10–12]. No effective agents exist
against resistant strains of many of these Gram-negative bacteria,
in particular, A. baumannii [12]. The Centers for Disease Control
and Prevention (CDC) estimates that over 23,000 people died in
United States of America in 2013 due to infections caused by resis-
tant strains of bacteria [6]. A recent comprehensive report suggests
that over 700,000 people die every year from drug-resistant infec-
tions world-wide [13]. The low and middle-income countries bear
the brunt of the burden of antibiotic resistance where an estimated
214,000 neonatal sepsis death per year is directly attributable to
antibiotic resistant bacteria [2,14]. The greatest burden: when no
safe and appropriate drug is available for treatment, an antibiotic
with low therapeutic index (e.g., polymyxin, colistin) is used to
treat certain infections such as multi-drug resistant A. baumannii
infection as a last resort [12]. New antibiotics with new modes of
action or a new chemical class with new target interactions and
an established mode of action are needed. The question is, why
are we where we are after the discovery of penicillin and many
other highly effective antibiotics between 1940 and 1962 [15].
What are the challenges? What have we learned? Is there a poten-
tial path forward? In this viewpoint we will discuss the challenges
and present our opinion along with that of others for a potential
path forward for discovery and development of new (ideal) antibi-
otics for treatment of resistant bacterial infections.
2. Brief review of key antibiotic classes
The true systematic discovery of antibiotics began after the for-
tuitous discovery of penicillin with the discovery of a number of
other natural product antibiotics from screening of microbial
extracts between 1940 and 1962 [1]. This led to the identification
of most of the chemical structures that became antibiotics them-
selves or served as chemical scaffolds for the discovery and devel-
opment of subsequent generations of antibiotics supporting
today’s antibiotic pipeline, with the exception of two new classes
approved after 2000 [15]. The major structural classes of clinical
antibiotics (Table 1) and overall impact of major classes are briefly
summarized here.
2.1. b-Lactam antibiotics
Major b-lactam antibiotics are represented by four classes-
penicillin, cephalosporin, carbapenem, and monobactams (Fig. 1).
With the exception of the monobactams, they are composed of a
bicyclic-fused ring system with a b-lactam ring being one of those
rings. The penicillins contain sulfur in the five membered second
rings, cephalosporins contain sulfur in the six membered second
ring, and carbapenems contain a carbon in the five membered sec-
ond ring. Monobactams do not contain a second ring. b-Lactam
antibiotics inhibit bacterial growth by inhibiting cell wall synthesis
via binding to a series of enzymes, penicillin-binding proteins
(PBPs) that synthesize and remodel peptidoglycan. They are broad
spectrum and highly effective antibiotics. These classes com-
manded tremendous efforts on chemical modifications affording
over 100 clinical agents in last 75 years [16].
Sequential and systematic structural diversification of the R
group in the penicillin class of antibiotics has led to the develop-
ment of over 20 clinically useful antibiotics including methicillin,
amoxicillin and piperacillin (Fig. 1). It is quite remarkable that
medicinal chemistry practitioners have synthesized improved
molecules, often with better spectrum and resistance profiles,
 S.B. Singh et al. / Biochemical Pharmacology 133 (2017) 63–73 65

Table 1
Major classes of antibacterial agents used in systemic therapy.

Drug Class Examples Target Pathway inhibited Spectrum

b-Lactams Meropenem, amoxicillin Multiple PBPs Cell wall synthesis Broad spectruma
Glycopeptides Vancomycin Lipid II Cell wall synthesis Gram-positive
Macrolides Erythromycin, azithromycin 50S RNA of ribosome Protein synthesis Gram-positiveb
Oxazolidinones Linezolid 50S RNA of ribosome Protein synthesis Gram-positive
Amphenicols Chloramphenicol 50S RNA of ribosome Protein synthesis Broad Spectrum
Lincosamides Clindamycin 50S RNA of ribosome Protein synthesis Gram-positive
Tetracyclines Doxycycline, tigecycline 30S RNA of ribosome Protein synthesis Broad Spectrum
Aminoglycosides Gentamicin, amikacin 30S RNA of ribosome Protein synthesis Broad Spectrum
Fluoroquinolones Levofloxacin, moxifloxacin Gyrase, Topoisomerase IV DNA synthesis Broad Spectrum
Nitroimidazoles Metronidazole DNA (?) DNA synthesis+ Broad Spectrum
Lipopeptides Daptomycin Membranes Membrane integrity Gram-positive
Polymyxins Colistin Membranes Membrane integrity Gram-negative
a
Broad spectrum indicates clinically useful activity against both Gram-positive and Gram-negative bacteria; some class members have narrower spectra.
b
Some macrolides have useful activity against fastidious Gram-negatives.

NH 2
S

OH N
H R H H
R H N H H
N S H
S N N
O 2 Me
O N R O
N R1 N O
O O O HO 2C N
CO 2H CO 2H CO 2H O SO3H
Penicillins(>20) Cephalosporins (>70) Carbapenems (>7) Monobactam (Aztreonam)
Me
N+
OMe HO H N O
N N H HO
H H
N H HO P N S H H
S O S N N H
MeO O
O N S N NH
N S S N
O O O
CO 2H CO 2H CO 2H

Methicillin Ceftaroline Imipenem

CO 2H
O
NH 2 N O O
H 2N N H HN HO
H H H N H H
N N S NH 2 NMe 2
S S N H
HO NH 2
O O S NH
N N N+ N N
O O O
CO 2H CO 2H CO 2H
Amoxicillin Ceftolozane Meropenem
NEt
O
N
O O
NH N O
H 2N N H HO
H H N H H H
N S NH
S S NH S O
O O N S
N NH NH H N O
N N 2
O O O
CO 2H CO 2H O CO 2H
P iperacillin Ceftobiprole Doripenem
Fig. 1. Chemical structures of selected numbers of b-lactam antibiotics.

one at a time just through modification at a single location of the
molecule [16].
The cephalosporin class (Fig. 1) of b-lactam antibiotics was sub-
ject to much more intensive systematic studies leading to over 70
clinical agents often with broader spectrum of activity and superior
resistance profile. Syntheses of a large number of improved cepha-
losporin antibiotics were realized only because beneficial chemical
diversification could be performed simultaneously at two struc-
tural sites of the molecule represented by R and R1. The resulting
cephalosporin antibiotics may be clustered into five groups based
on R and R1 substitution types, spectrum and resistance profiles.
Ceftaroline, and ceftobiprole (approved in EU) are the latest
(2010–2015) broad-spectrum fifth generation cephalosporins
entered into clinical practice (Fig. 1) [16].
Thienamycin, the first member of the carbapenem class of
b-lactam antibiotics, was discovered in the 1970’s and a derivative
(imipenem in combination with the renal dehydropeptidase I
inhibitor, cilastatin) was first approved for clinical use in 1985.
66 S.B. Singh et al. / Biochemical Pharmacology 133 (2017) 63–73
H HO O
O OH S H 2N
N N
N N
N N
O O
CO 2H CO 2H
Cla vu la n ic a c id Tazobactam
Fig. 2. Chemical structures of selected b-lactamase inhibitors.
Imipenem (Fig. 1) is one of the most potent and broadest spectrum
antibiotics that remain in clinical use as a reserved antibiotic for
treatment of infections caused by imipenem susceptible strains
of Gram-negative and Gram-positive bacteria including P. aerugi-
nosa and A. baumannii. Subsequently, additional modifications
including addition of a b-methyl group at C-2 of the five-
membered core ring along with modifications of R groups allowed
for development of six additional carbapenem antibiotics (panipe-
nem, ertapenem, biapenem, meropenem, doripenem, and tebipe-
nem) with partially overlapping and/or varying antibacterial
spectrum, properties and safety profile to provide alternatives for
treatment of serious infections [16].
Aztreonam, the only marketed member of the monobactam
class (so called because of the lack of a second fused ring) has an
exclusively Gram-negative spectrum. It is not active against
Gram-positive and anaerobic bacteria due to its PBP-binding char-
acteristics. Monobactams are unique among b-lactams in being
non-susceptible to hydrolysis by class B metallo-b-lactamases
(MBL). Indeed, resistance to all b-lactams except aztreonam is a
handy marker for MBL-producing bacteria. Because many bacteria
produce b-lactamases of multiple classes and aztreonam is suscep-
tible to BLs of classes A and C, it is not a universal solution for the
MBL problem [16].
Some of the latest members of the penicillins, cephalosporins
and almost all of the carbapenems continue to be used for treat-
ment of susceptible bacteria. However their utility as standalone
antibiotics is eroding due to increasing resistance because of
expression of PBP2x in Gram-positive (e.g., PBP2a in MRSA) and
derepressed or acquired b-lactamases in Gram-negative bacteria
[17]. b-Lactamases are enzymes that inactivate b-lactam antibi-
otics by hydrolytically opening the b-lactam ring, making them
unavailable for binding to PBPs and thus preventing their inhibi-
tion of bacterial growth [17,18]. Four classes of b-lactamases (class
A, B, C and D) are expressed in different Gram-negative bacterial
species [17,18].
Fortunately, a strategy employed since the 1980’s leads to inhi-
bition of these hydrolytic enzymes by even more reactive elec-
trophilic b-lactamase inhibitors, thus sparing b-lactam antibiotics
from b-lactamases [19]. The first of the b-lactamase inhibitors,
clavulanic acid (Fig. 2), a b-lactam-containing molecule lacking
intrinsic antibacterial activity, was discovered and approved in
combination with amoxicillin for the treatment of infections
caused by certain Gram-negative bacteria producing class A serine
b-lactamases [19]. The combination agent restored most of the
original amoxicillin activity against Gram-negative bacteria. This
led to development of the extended spectrum b-lactamase inhibi-
tor, tazobactam, which in combination with piperacillin restored
the original activity of piperacillin against Gram-negative
pathogens expressing class A b-lactamase enzymes [19]. More
recently tazobactam has been marketed in combination with the
cephalosporin ceftolozane, which has a modified side-chain at
the 3-position of the cephem nucleus that adds potent anti-
pseudomonal activity. After recent discovery efforts failed to pro-
duce a new class of antibacterial agents to treat resistant ESKAPE
pathogens, significant effort was expended on the discovery of
new b-lactamase inhibitors. This effort resulted in the discovery
of the new diazabicyclooctane (DBO) class (Fig. 2) of extended
O HN O
H
N
N
H
N S O B CO 2H
HO O
N N
O O SO3H O O SO3H
Avibactam Relebactam Vaborbactam
spectrum b-lactamase inhibitors with inhibition of classes A, C
and some class D b-lactamases. This class of inhibitors is repre-
sented by avibactam and relebactam (Fig. 2). Avibactam restores
most of the Gram-negative activity of ceftazidime, a cephalosporin.
The combination was approved for human use in 2015 [20]. The
imipenem-cilastatin-relebactam combination restores most of
the imipenem activity against P. aeruginosa and many other
Gram-negative pathogens harboring resistance due to expression
of class A and C b-lactamases. Imipenem-relebactam combinations
along with several other b-lactamase inhibitors of DBO class as
well as a boron containing inhibitor (vaborbactam) are in clinical
development [20]. Unfortunately even this strategy has not yet
been amenable for development of an inhibitor of class B
metallo-b-lactamase inhibitors to treat NDM-1 or other types of
resistance owing to metallo-beta-lactamase-producing pathogens.
Meiji Pharma has published on their MBL-inhibitor ME-1071, but
the spectrum [21] of inhibition does not appear to extend much
beyond the IMP family and it is unclear if development is continu-
ing. Besides inhibiting the metallo-beta-lactamases directly,
another approach is to partner a class A/C BLI with an antibiotic
inherently non-susceptible to hydrolysis such as aztreonam
(ATM). Indeed the combination of ATM and avibactam reached
phase I stage of clinical development (clinicaltrials.gov, 27 Septem-
ber 2016), though reports on in vitro activity indicated the spec-
trum may not be sufficient for MBL-producing P. aeruginosa.
Clearly in the absence of a new class of antibiotics to provide
treatment of ESKAPE pathogens restoring the activity of workhorse
b-lactam antibiotics is a sound approach for treating resistant
Gram-negative infections. However this approach does not fully
restore the activity of critical b-lactam antibiotics because of pres-
ence of other resistance mechanisms in many Gram-negative
pathogens.
2.2. Glycopeptides
Vancomycin (Fig. 3) is a natural product antibiotic that binds to
the terminal dipeptide, D-alanine-D-alanine, of Lipid II, a precursor
of the peptidoglycan chain of the bacterial cell wall, thus prevent-
ing cell wall synthesis [22]. It is an effective broad-spectrum Gram-
positive agent used to treat infections of methicillin susceptible as
well as methicillin resistant S. aureus and other Gram-positive
infections in the hospital [22]. For a while, vancomycin was consid-
ered an antibiotic of last resort and remains critical for treatment
of Gram-positive infections including MRSA. However its utility
is being diminished against Enterococcus faecalis and E. faecium
infections due to an increasing rate of resistance. Vancomycin is
also effective as an oral formulation for treatment of Clostridium
difficile associated diarrhea (CDAD). In 2009, telavancin, a more
lipophilic derivative of vancomycin, was approved for treatment
of acute bacterial skin and skin structure infections (AbSSSi)
caused by Gram-positive infections including MRSA. It has a long
half-life in humans of 9 h allowing for once daily dosing. Subse-
quently it was also approved for hospital-acquired pneumonia
but only as a second line treatment [20,23]. Telavancin retains
activity against vancomycin-resistant bacterial strains due to the
VanB mechanism but not against VanA strains. Recently, dalba-
vancin and oritavancin, two newer more potent glycopeptide
 S.B. Singh et al. / Biochemical Pharmacology 133 (2017) 63–73 67

Cl
HO NH NH
2
HO
O O
O O O O
O H 2N O
Cl Cl
O O HO O O O

HO OH OH
Cl O Cl O
O O H O O H
H H H H
N N N N N N
O N O N
N N N N
H H H H H H
NH O O NH O O
H 2NOC H 2NOC
HO 2C HO 2C
OH OH
HO Vancomycin HO Oritavancin
O
OH
OH
CO 2H N CO 2H
O H O
O H O
N O O
H 2N N NH
H CO 2H
NH O OH
O HO Cl
O O O
H H
HN HO 2C NH O N N
HN N N NH
H O H H O
H O O H NH O O
HN N N Me 2N Cl
N O HN N NHMe
OH
O H
O O O H O HO O
CONH 2 N O O
NH HO OH
HO O HO
O OH
CO 2H OH
NH 2 O OH

Daptomycin Dalbavancin

Fig. 3. Chemical structures of selected glycopeptides and lipopeptide antibiotics.

H 2N H
H 2N N
HO NH HO
HO NH
O
OH O O
OH
O NH 2
CHO HN NH 2 NH 2 OH
H 2N H 2N H
O NH 2 O N
HN NH 2
OH O HO HO
NM 2 O
OH O O
O OH
HN HN
HO OH OH
S isomicin Plazomicin

Fig. 4. Chemical structures of selected aminoglycoside antibiotics.

antibiotic analogs with improved properties were approved by reg-
ulatory agencies for treatment of Gram-positive infections supple-
menting vancomycin in clinic [20,23]. Dalbavancin and oritavancin
(Fig. 3) are significantly more potent and have over a 300 h human
half-life, leading to a significant dosing advantage for treatment of
AbSSSi, infusion of just a single dose (1000–1500 mg) compared to
twice daily infusion of vancomycin. Both of these compounds are
approved for treatment of vancomycin-sensitive strains of bacteria
including Enterococcus sp. Dalbavancin is a semisynthetic deriva-
tive of A40926 factor B, a teicoplanin type natural product,
whereas oritavancin is a semisynthetic analog of chloroere-
momycin, a vancomycin type glycopeptide. Like vancomycin, dal-
bavancin and oritavancin bind to D-ala-D-ala but unlike
vancomycin, they gain secondary interaction with the cell mem-
brane [24,25]. Additionally, oritavancin binds to the pentaglycyl
bridging segment of S. aureus peptidoglycan [25]. The lipophilic
structural features of these two agents not only increase half-life
in humans but also provide additional target(s) interactions
accounting for improved potency [20,24,25]. The antibacterial
spectra of dalbavancin and oritavancin are generally similar to van-
comycin including its cross-resistance profile except against
vancomycin-resistant strains. Dalbavancin shows in vitro cross-
resistance to the VanA phenotype of E. faecalis and E. faecium
(VRE) but lower levels of cross-resistance the VanB phenotype of
VRE [26]. Oritavancin does show some cross-resistance to the VanA
phenotype VRE (E. faecalis, MIC90 of 0.5 lg/mL and E. faecium,
MIC90 of 0.06 lg/mL) but no cross-resistance to VanB phenotypes
(E. faecalis, MIC90 of 0.015 lg/mL and E. faecium, MIC90 of
60.008 lg/mL), due to acquisition of additional binding interac-
tions [27]. While none of the two compounds have been approved
for the treatment of infections by VRE strains oritavancin has
potential to be used for such treatments.
2.3. Lipopeptide
Daptomycin (Fig. 3) is a natural lipopeptide, that is potent,
broad-spectrum and rapidly bactericidal Gram-positive agent that
is not cross-resistant to any of the other clinically used antibacte-
68 S.B. Singh et al. / Biochemical Pharmacology 133 (2017) 63–73

rial agents due to its novel mode of action [28]. Mechanistically,
daptomycin is inserted into the cell membrane causing depolariza-
tion and formation of holes, leading to ion leakage and disruption/
rupture of the cell membrane and bacterial death. Daptomycin is a
highly successful intravenous antibiotic for treatment of nosoco-
mial Gram-positive infections including MRSA and VRE strains
[28].
sisomicin [20] which is less susceptible to many aminoglycoside
resistance mechanisms, is currently undergoing phase III develop-
ment and has been granted fast track designation for treatment of
serious and life-threatening carbapenem resistant Enterobacteri-
aceae (CRE) infections. (www.achaogen.com, September 4, 2016).
2.5. Tetracyclines

2.4. Aminoglycosides Tetracyclines (Fig. 5) are another old class of broad-spectrum

Aminoglycosides were discovered in the Golden age of antibi-
otic discovery-the first member being streptomycin (Fig. 4). More
than 8 members of this family of antibiotics have been used in clin-
ical practice for treatment of both Gram-positive and Gram-
negative bacteria due to their broad-spectrum activity [29]. They
bind to the 16S rRNA subunit of the 30S ribosome and inhibit bac-
terial protein synthesis [29]. A number of aminoglycosides were
used in the clinic in the past but they have fallen out of favor not
only due to resistance development but also due to reversible
nephrotoxicity and irreversible ototoxicity [30]. An improved
aminoglycoside, plazomicin (Fig. 4), a semisynthetic derivative of
antibiotics [31]. Ten members of this class of antibiotics have been
in clinical practice for more than 60 years. They are inhibitors of
bacterial protein synthesis due to binding to the 16S rRNA of the
30S ribosomal subunit. Significant class-based resistances due to
expression of tetracycline-specific efflux pumps and ribosome-
protection mechanisms have reduced the effectiveness of tetracy-
clines [31]. However tigecycline (Fig. 5), a glycylcycline, is a
broad-spectrum agent that evades most bacterial tetracycline-
specific efflux pumps and other tetracycline resistance
mechanisms. With the successful launch of tigecycline, several
other tetracycline semisynthetic derivatives with broad-spectrum
activity are being evaluated in phase III clinical trials [20,30].

HO N N N
H H H H
OH OH
O
H
NH 2 N NH 2
N
OH H OH
OH O OH O O OH O OH O O

Tetracycline Tigecycline

O
N
N N N F N
H H H H H H
OH OH OH
O
H
NH 2 N NH 2 N NH 2
N
OH OH H OH
OH O OH O O OH O OH O O OH O OH O O

S arecycline Omadacycline Eravacycline

Fig. 5. Chemical structures of selected tetracycline antibiotics.

O O
Me
HO N
HO OH HO OMe HO OH
OH NMe 2 OH NMe 2 NMe 2
HO O HO O HO O
O O O O O O

O O O O O O O O O

O OH O OH O OH

Erythromycin Clarithromycin Azithromycin

O N O
N
N N O N N N O N
H 2N OMe
OMe
O O NMe 2
NMe 2
HO HO O
O O O
O O

O O O O
F

Telithromycin S olithromycin
Fig. 6. Chemical structures of selected macrolide antibiotics.
 S.B. Singh et al. / Biochemical Pharmacology 133 (2017) 63–73
Sarecycline (Fig. 5) is being studied for treatment of acne whereas
the omadacycline (Fig. 5) is being evaluated for AbSSSi and
community-acquired bacterial pneumonia (CABP) [20]. After the
development of an efficient convergent total synthesis of tetracy-
cline [32,33], it became possible to design compounds that were
not easily obtained via semisynthetic routes leading to the synthe-
sis of eravacycline (Fig. 5), the first C-7, C-9-disubstituted fluorocy-
cline with broad-spectrum antibacterial activity including MDR
bacteria [20,30]. Bacterial strains harboring tetracycline efflux
pumps are susceptible to eravacycline. It is also active against
many multiple drug resistant Gram-negative bacterial strains.
Eravacycline is being studied in phase III trials for treatments of
cIAI and cUTI (www.tetraphase.com, September 4, 2016).
2.6. Macrolides
Macrolides (Fig. 6) have been in clinical use for more than five
decades for the oral treatment of community-acquired respiratory
infections [34]. They inhibit bacterial protein synthesis due to
binding to the 23S rRNA of the 50S ribosomal subunit [35]. More
than 14 members of the macrolide class have been in clinical use
and three key members of the macrolide family, namely ery-
thromycin, clarithromycin, and azithromycin (Fig. 6), play critical
roles in the treatment of respiratory tract infections [34]. However
their use is hampered due to development of macrolide resistance
in S. pneumoniae. Ketolide derivatives overcome this resistance,
leading to approval of the first ketolide, telithromycin (Fig. 6).
Unfortunately, its use was severely restricted by FDA in a post-
approval decision due to adverse events. Solithromycin (Fig. 6) is
another semisynthetic ketolide that has completed two-phase III
trials for CABP [20,30]. Both trials met primary end points and have
been under FDA regulatory review (www.cempra.com, September
4, 2016). Recently, as with tetracycline, a highly convergent gen-
eral total synthesis of the macrolide class of compounds has been
reported [36] that is currently being exploited from a commercial
perspective (www.macrolide.com). The newly minted synthetic
route may enable synthesis of diverse analogs of macrolides not
easily achieved by semisynthesis routes and may allow a renais-
sance of macrolides that overcome resistance.
2.7. Oxazolidinones
Oxazolidinones are the newest class of synthetic antibacterial
agent represented by linezolid (Fig. 7), the first FDA approved oxa-
zolidinone in 2000 [20,37]; a second member, tedizolid, was
approved in 2014 [20]. Linezolid is a broad-spectrum Gram-
positive agent demonstrating efficacy against MRSA infections. It
is an inhibitor of protein synthesis due to binding to the 23S rRNA
of the 50S ribosomal subunit [35]. It is indicated for treatment of
serious Gram-positive infections. While linezolid resistance does
occur, it is not (yet) prevalent; however the utility of linezolid is
limited to short term treatment (less than 2 weeks) due to reversi-
ble myelosuppression resulting from inhibition of mammalian
mitochondrial protein synthesis. Overcoming resistance and
myelosuppression provided impetus for the discovery and devel-
opment of second generation oxazolidinones, leading to approval
of tedizolid (Fig. 7) phosphate in 2014 for treatment of
O O
O O N N
O N N H
N N N
F F
Linezolid Tedizolid phosphate
Fig. 7. Chemical structures of oxazolidinone antibiotics.
69
Gram-positive ABSSSI by once daily dosing for a 6 day duration
compared to linezolid’s 10 days [20,30]. Tedizolid is more potent
than linezolid in vitro and shows activity against some linezolid-
resistant strains, especially those carrying the horizontally trans-
mitted cfr resistance determinant [38]. Tedizolid is a bactericidal
agent in vivo and is not cross-resistant with linezolid-resistant bac-
terial strains. Tedizolid does not interact with eukaryotic mito-
chondria and has the potential for a better safety profile that
must be confirmed in clinic [39]. Radezolid (Fig. 7) is another oxa-
zolidinone analog undergoing phase II clinical development. Sev-
eral other oxazolidinones are in earlier stages of clinical
development [20,30].
2.8. Quinolones
Quinolones, exemplified by nalidixic acid (actually a naph-
thyridine) (Fig. 8) are a class of synthetic antibiotic that have been
used for treatment of bacterial infections for over 35 years [40].
Fluoroquinolones were introduced as a second-generation of qui-
nolones in 1980’s showing improved potency and antibacterial
spectrum. The class became a significant contributor to treatment
of bacterial infections including major Gram-negative strains such
as Pseudomonas aeruginosa. Over 30 quinolones have been
approved for clinical use. The most commonly used broad-
spectrum fluoroquinolones are represented by ciprofloxacin and
levofloxacin (Fig. 8) [40]. Quinolones are bactericidal and inhibit
bacterial growth by inhibiting the bacterial DNA synthetic
enzymes DNA gyrase and topoisomerase IV [40]. Bacteria have
developed significant resistant to the quinolones by mutation at
one or both of the target binding sites. Newer quinolones having
more balanced activity against DNA gyrase and Topoisomerase
IV, such as moxifloxacin, are less susceptible to resistance selec-
tion. Ten quinolone antibiotics have been approved out of the total
of 32 total antibiotics approved by regulatory agencies between
200 and 2015 [20]. Three new quinolones are in phase III and
two in phase II clinical development [20]. The latest approved qui-
nolone antibiotics are nemonoxacin, finafloxacin and ozenoxacin
(Fig. 8) [20]. In addition to the quinolone class of antibiotics, the
gyrase and topoisomerase IV dual targets bind and are inhibited
by a variety of other chemical classes of small drug-like molecules
including non-quinolone bacterial topoisomerase inhibitors
(NBTIs) and ETX0914 [41]. While none have yet been approved
for clinical use, gepotidacin and ETX0914 (Fig. 8) are in phase II
clinical development for treatment of gonorrhea [20].
3. Challenges for discovery of an ideal new antibiotic without
cross-resistance
3.1. Finding new chemical matter for an antibiotic lead
As has been discussed above all antibiotics are natural products
or their semi-synthetic derivatives and synthetic analogs of oxazo-
lidinone and quinolones. The derivatives have been derived by
incremental improvement of antibiotic properties via step-wise
chemical modification of various classes of natural product antibi-
otics as well as the oxazolidinone and quinolone [1,20,42]. These
chemical modifications were based on empirical structure activity
H O
N
O N O O
N N N H
OPO3H 2 N N
H
F
Radezolid
70 S.B. Singh et al. / Biochemical Pharmacology 133 (2017) 63–73
Fig. 8. Chemical structures of selected quinolone and non-quinolone DNA topoisomerase II inhibitor antibiotics.
studies as well as incorporating structure-based design elements,
wherever structural information was available. Identifying new
antibiotics with improved antibiotic spectrum and resistance prop-
erties via further structural changes to the aforementioned struc-
tural classes is facing significant challenges due to lack of
additional beneficially modifiable chemical sites. In addition,
class-based resistance is inevitable. These issues are of foremost
concern to antibiotic discovery scientists worldwide. Large phar-
maceutical companies were very active in making new antibiotics
when chemical leads were abundantly available for medicinal
chemistry improvement. But there has been a significant decrease
in delivery of new improved antibiotics by chemical modifications
of the old chemical lead classes and by failure of lead generation
from screening of chemical libraries (from in-house pharmaceuti-
cal companies as well as publically available chemical libraries).
This creates a monumental challenge and seriously hampers
A = Acve transporters
Gram-posive Gram-negave B = SM efflux pumps
C = OM diffusion pore
D = OM general porin
LPS E = RND efflux
Pepdoglycan (SM = Single Membrane)
Outer
C D Membrane (OM)
Cytoplasmic
A B A B E Membrane
Fig. 9. Differences between Gram-positive and Gram-negative permeability barri-
ers. Gram-positive and Gram-negative envelopes: A = active transporter; B = single
membrane efflux pumps; C = outer membrane facilitated diffusion pore; D = outer
membrane general porin; E = RND efflux pump spanning both outer and cytoplas-
mic membranes. All five A–E (transporters, efflux pumps, diffusion pore and porin)
are present in Gram-negative bacterial strains whereas only active transporter (A)
and single membrane efflux pump (B) is present in Gram-positive bacterial strains.
Many Gram-positive agents show weak or no activity against Gram-negative
bacterial strains because of the outer membrane barrier or the action of efflux
pumps. If outer membrane is breached or efflux inactivated, such compounds gain
Gram-negative activity.
abilities of pharmaceutical companies to pursue antibiotic discov-
ery efforts without disproportionate use of resources that could be
applied in other therapeutic areas with readily available biological
target-chemical lead pair starting points for medicinal chemistry.
The lack of quality new antibiotic chemical leads (e.g., in compar-
ison to historical leads which often possessed desired developable
antibacterial spectrum) suitable for starting medicinal chemistry
programs was debated within pharmaceutical companies for many
years, fortunately now it is being debated outside of the pharmaceu-
tical industry at many public forums [41,43,44]. This is a critical step
for broadcasting the challenges and educating people outside of the
antibiotic field, and, most importantly, bringing the issues to the
attention of decision makers at funding institutions. In the end it is
the lack of new quality chemical antibacterial starting point leads that
is the biggest roadblock for new antibiotic discovery.
3.2. The problem of entry into and retention of antibacterial chemicals
The cellular machinery of Gram-positive and Gram-negative
bacteria is surrounded by protective membranes. A single
cytoplasmic membrane layer in addition to a thick, rigid cell wall
(peptidoglycan) protect Gram-positive bacteria whereas Gram-
negative bacteria have a thinner peptidoglycan layer sandwiched
between two membranes, the cytoplasmic membrane (CM) and
an outer membrane (OM) (Fig. 9) [45]. These differences in the
protective cellular structure are the root cause of problems in dis-
covery of anti Gram-negative drugs [45]. Compounds inhibiting
intracellular targets must cross these membranes. The OM consists
of an asymmetric bilayer that comprises an outer leaflet of
lipopolysaccharide (LPS) and an inner leaflet of phospholipids –
together making the OM relatively impervious to both hydropho-
bic and hydrophilic compounds (Fig. 9) [45]. To allow passage of
required nutrients, it is traversed by water-filled channels called
porins, which are selective for hydrophilic, charged compounds
[46]. On the other hand, the CM is permeable to hydrophobic com-
pounds but allows limited diffusion of hydrophilic compounds. To
 S.B. Singh et al. / Biochemical Pharmacology 133 (2017) 63–73
enable uptake of required hydrophilic and other nutrients, the CM
contains solute-specific active transport systems such as perme-
ases. Compounds that can cross the OM may be expelled by efflux
pumps whose substrates appear to be small and hydrophobic or
large and zwitterionic [47]. Thus, large molecules are excluded
by size limitation of porins; lipophilic molecules that could pene-
trate the CM may not be allowed entry by the OM and may be sub-
ject to efflux pumps. Small hydrophilic molecules, particularly with
weak positive charge, can cross the OM and enter the periplasm
and are possibly less subject to efflux pumps, but are unlikely
allowed entry by CM. It might be said that the OM, CM and efflux
pumps are selective for uptake of solutes that are needed for bac-
terial survival but tend to exclude chemicals that are foreign to
bacteria [45]. The question arises: how do any of the existing
Gram-negative antibiotics get into the cytoplasm given the orthog-
onal sieving properties of the membranes and pumps? While there
are certain exceptions, the existing cytoplasmically targeted
antibiotics appear to have properties allowing diffusion through
both the porins of the OM and the phospholipid bilayer of the
CM. Detailed systematic studies leading to development of guideline
of principles of permeability (entry) and efflux is critically needed for
successful and efficient development of Gram-negative antibiotics.
To compound this challenge, cell membranes of all Gram-
negative pathogens are not identical. In some cases differences
are quite significant.
4. Multi target vs single target
It is inevitable that all antibiotics will develop resistance sooner
or later. Empiric observation of cumulative data on existing antibi-
otics suggest that antibiotics interacting with more than one bio-
logical targets (protein, RNA, DNA) have lower propensity for
target-based resistance than those targeting a single enzyme target
[48]. While the in vivo rate of resistance is more complex it is likely
that an antibiotic that binds to a single target will rapidly select
pre-existing target mutations that arise at a measurable rate per
generation [48]. In fact, selection of target mutations is a technique
used for mechanism of action determination of antibiotics. Exam-
ples of multi-targeting are the multiple penicillin binding proteins
targeted by b-lactams, Gyrase/topoisomerase IV that are targeted
by quinolones, and the rRNA of ribosomes targeted by many pro-
tein synthesis inhibitors that is the product of many rRNA cistrons.
The incorporation of structural elements in oritavancin and dal-
bavancin endowing them with additional binding interactions to
other targets led to improved potency and spectrum validating
another advantage of multi-targeting. In addition, this example
directly addresses the idea that additional binding sites can be
crafted in certain molecules, particularly in larger molecules, by
structure modification to potentially bring in additional interaction
with the same target and/or engagement to another target. A sim-
ilar argument can be made for the U-shape binding of the natural
product kibdelomycin to the active site as well as many backbone
interactions with Gyrase B and ParE proteins [49,50]. These inter-
actions likely lower the rate of resistance in S. aureus compared
to other Gyrase B and ParE inhibitors [51]. Therefore, it is expected
that ideal antibiotics would likely bind to more than one target or
at least will bind to targets with multi-point polar contacts not
only at the active site but also with the backbone of the target.
While the latter approach needs clinical validation, it is worth con-
sidering until abundant chemical leads become available.
5. Broad-spectrum vs narrow spectrum
Broad-spectrum antibiotics (Table 1) are often ideal for empiri-
cal treatment of bacterial infection [5]. In the absence of knowl-
71
edge of the causative bacterial strains, they should cover all
likely bacterial pathogens for a given site of infection. Traditional
culture-based strain identification takes 24–48 h, which presents
treatment challenges for seriously ill patients if empiric treatment
is not rapidly applied. Broad-spectrum antibiotics, particularly oral
antibiotics, do have disadvantages as they often inhibit growth of
anaerobic gut bacteria leading to imbalance in the bacterial popu-
lations of gut flora causing disease conditions (e.g., Clostridium dif-
ficile associated diarrhea, CDAD). Use of both a broad-spectrum
Gram-positive and Gram-negative agent is a second option where
seriously ill patients can be dosed with two antibiotics concomi-
tantly. A few agents do provide treatment coverage for most
Gram-positive infections including many commonly occurring
drug-resistant strains but such an option does not exist for treat-
ment of many drug-resistant Gram-negative bacteria [44]. It can
be argued that narrow spectrum (affecting one or a few similar
species) agents may be easier to discover and should be better/
safer as they will likely affect only bacterial populations that cause
disease without affecting beneficial bacterial populations. How-
ever, the challenges of development of narrow-spectrum or
strain-specific agents should not be minimized, as many targets
are common (similar) in most bacteria. While the spectrum of such
an agent may appear narrow, variable target inhibitory activities
due to differences in target binding and/or target access (based
on differences in cell envelope structure), may lead to drastically
different MIC values. Therefore, at a given dose, complete growth
inhibition of the major targeted strain can be achieved while lead-
ing to only partial inhibition of less sensitive strains. This situation
may lead to selection of resistance in the partially inhibited popu-
lations. This may theoretically create problems - but not always.
For example, partial inhibition of Pseudomonas aeruginosa by erta-
penem has not resulted in an increase in resistance of Pseu-
domonas to other antibiotics including carbapenems [52]. One-
way this might be potentially circumvented is by identification/
selection of strain-specific targets and development of individual
antibiotics inhibiting those targets on a strain-by-strain basis.
However, this target-specific approach, if not multi-targeted, has
the downside of likely leading to rapid resistance selection.
In any event, strain specific and super narrow antibiotics have
to be coupled with rapid diagnostics for this strategy to be success-
ful. In addition regulatory agencies must make a paradigm shift to
allow strain-based clinical trials and approval vs current disease-
based trials and approval. If successful, the treatment and manage-
ment of monomicrobial bacterial infections will be changed likely
for better. However, treatment of polymicrobial infections will
require concurrent administration of a second complementary
antibiotic or broad-spectrum antibiotic. None of this will help dis-
covery of quality antibiotics until a quality chemical lead-target
pair is identified. However, once such a quality chemical lead-
target pair is identified, this approach may simplify the process
of lead optimization and may potentially reduce the cost of clinical
development. Unfortunately, this approach will also segment the
patient population for individual antibiotics and would likely lead
to significantly higher cost of treatment unless new pricing strate-
gies are developed.
6. New target-lead pair and new lead-old target pair
Most of the established antibiotic targets are generally privi-
leged targets affected by specific inhibitor classes with the excep-
tion of the bacterial topoisomerase II target (see below). For
example, the active sites of penicillin-binding proteins interact
with b-lactam antibiotics, the D-ala-D-ala binding site interacts
with glycopeptides, specific ribosomal sites interact with macro-
lides, tetracycline, and aminoglycosides (Table 1). These molecular
72 S.B. Singh et al. / Biochemical Pharmacology 133 (2017) 63–73
interactions tolerate chemical modifications only on a narrow por-
tion of the antibiotic molecule leaving the major portion of the
chemical structure untouchable (see examples in Section 2, above).
Peptidoglycan and ribosomes are large biological structures that
contain many antibiotic targets; they can be potentially interro-
gated by a variety of chemical matter through individual
inhibitor-target pairs that appear to be privileged. Therefore de
novo design or natural product based alternate binders/inhibitors
to the clinically validated privileged sites has not been successful.
Many other peptidoglycan or protein synthesis inhibitors targeting
other binding sites have been reported but have not been advanced
to clinical practice. Bacterial topoisomerase II target is the rare
exception. It is composed of four proteins, Gyrase A, B, topoiso-
merases IV (ParC and ParE). The highly successful quinolone class
of antibiotics (targeting Gyrase A/ParC) as well as the coumarin
(Gyrase B/ParE) class of natural product antibiotics binds/inhibits
these dual target pairs (Gyrase A/ParC and gyrase B/ParE). Because
of the wide tolerance for binding with biologically functional con-
sequences a variety of structural classes have been identified and
optimized to broad-spectrum antibiotics exemplified by the Phase
II clinical agents gepotidacin and EXT0914 [20]. Many other inhibi-
tors have been reported that interact with these targets at different
sites [41].
7. Potential path forward for a new ideal antibiotic
With identification of challenges, several teams started analyz-
ing the chemical structure of antibiotics by computational analysis
listed in the Chemical, Manufacturing, and Controls (CMC) data-
base of FDA approved drugs and compared them with the FDA
approved non-antibiotic drugs listed in the CMC database. All the
analyses indicated clear differences in the physical properties of
antibiotics vs other drugs. From these analyses it was also dis-
cerned that Gram-positive agents fall in a significantly different
property space than Gram-negative agents. Based on the cumula-
tive analysis the general conclusion is that Gram-positive agents
have larger molecular weight, larger polar surface area (243 vs
70), and lower C log D7.4 ( 0.2) than CMC drugs (1.6) [45]. The data
for Gram-negative drugs were dramatically different from Gram-
positive agents. The Gram-negative agents are generally smaller,
more polar and charged with the C log D7.4 for Gram-negative being
2.8 [45,53]. Most compounds in general compound libraries orig-
inate from other human-health drug discovery programs and
mostly consist of simple flat, achiral, and lipophilic structures that
have been loosely designed for oral bioavailability, thus requiring a
different set of properties from antibacterials as evidenced by com-
parison of the CMC database and antibiotics. The differences of
physical properties of antibiotics in comparison with other drugs
underscore the issue of why screening of chemical libraries
(excluding known antibiotic classes) do not produce quality antibi-
otic cell-active hits. While any molecules with general physical
properties of antibiotics cannot be assured to have antibiotic activ-
ity, inclusion of diversified complex structures with many func-
tional groups can provide a reasonable opportunity, but no
guarantee of success. Therefore, completely new libraries should
be designed and synthesized keeping in mind the physical proper-
ties of antibiotics, incorporation of a variety of functional groups
embedded in complex three-dimensional natural product-like chi-
ral structures, particularly for Gram-negative agents. This is a big
task for any single commercial organization to undertake and
therefore would require a collective approach in precompetitive
space. In this context, The Pew Charitable Trusts have issued a
position paper on June 21, 2016 on ‘‘A scientific roadmap for antibi-
otic discovery-A sustained and robust pipeline of new antibacterial
drugs and therapies is critical to preserve public health” in which
not only scientific issues underlying lead generation have been
highlighted but also a consortium approach has been advocated
for design and synthesis of new chemical matters with antibiotic
like properties along with other discovery/cell based screening
approaches has been discussed (www.pewtrusts.org).
In order to discover ideal antibiotics, whether broad-spectrum or
narrow spectrum, new leads must be discovered. Chemical antibiotic
leads can come from synthetic matter discussed above or from revis-
iting natural products. Both traditional and genetic based natural
product approaches should be considered as part of the overall goal.
Many shortcomings of natural product antibacterial discoveries can
now, with modern methods, be addressed rapidly and efficiently.
Cell based screening approaches are critical for discovery of new
quality chemical matters for further medicinal chemistry optimiza-
tion. Multi-targeting is key for a lower rate of resistance, which is
an important a criterion for advancing a lead into clinic for develop-
ment of an ideal antibiotic regardless of spectrum.
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