Biochemical Pharmacology xxx (2016) xxx–xxx

Contents lists available at ScienceDirect

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

Review

History of antimicrobial drug discovery – Major classes and health

impact
Rustam Aminov
School of Medicine and Dentistry, University of Aberdeen, Aberdeen AB25 2ZD, United Kingdom

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

Article history: The introduction of antibiotics into clinical practice revolutionized the treatment and management of
Received 25 August 2016 infectious diseases. Before the introduction of antibiotics, these diseases were the leading cause of mor-
Accepted 4 October 2016 bidity and mortality in human populations. This review presents a brief history of discovery of the main
Available online xxxx
antimicrobial classes (arsphenamines, b-lactams, sulphonamides, polypeptides, aminoglycosides, tetra-
cyclines, amphenicols, lipopeptides, macrolides, oxazolidinones, glycopeptides, streptogramins, ansamy-
Keywords: cins, quinolones, and lincosamides) that have changed the landscape of contemporary medicine. Given
Antimicrobial drug discovery
within a historical timeline context, the review discusses how the introduction of certain antimicrobial
History
classes affected the morbidity and mortality rates due to bacterial infectious diseases in human popula-
tions. Problems of resistance to antibiotics of different classes are also extensively discussed.
Ó 2016 Published by Elsevier Inc.

1. Introduction 2. Arsphenamines and the foundation of modern antimicrobial

The highest rate of decline in infectious disease mortality in the
USA was recorded for a period of 15 years, from 1938 to 1952,
when the annual mortality rate due to infectious diseases was
rapidly decreasing, by 8.2% per year [16]. Infectious diseases that
mostly contributed to this sharp decline were pneumonia, influen-
za, and tuberculosis. These declines corresponded to the introduc-
tion into clinical practice of sulphonamides in 1935, penicillin in
1941, and streptomycin in 1943, with a number of other combina-
tion drugs, such as para-aminosalicylic acid in 1944 and isoniazid
in 1952, introduced for tuberculosis treatment in addition to strep-
tomycin [21]. This correlation clearly indicates the importance of
antimicrobials in the control of infectious diseases. A recent statis-
tics also reflects our success in dealing with infectious diseases that
now cause much less mortality compared to many other diseases
of a non-infectious nature. In the most recent National Vital Statis-
tics Reports, among the 15 leading causes of death in the USA,
infectious diseases, such as influenza and pneumonia, are super-
seded by heart disease, cancer, chronic lower respiratory diseases,
accidents, stroke, Alzheimer’s disease, and diabetes [245]. The
foundation for this success in confronting death from infectious
diseases was built by formidable scientists, who made important
antimicrobial drug discoveries and are greatly acknowledged for
saving numerous lives.
E-mail address: rustam.aminov@abdn.ac.uk
chemotherapy
Paul Ehrlich’s idea of a ‘‘magic bullet”, which is highly selective
and targets only the disease-causing microorganisms, came to him
while he was working with an extensive range of aniline and other
synthetic dyes that became available as a result of the rapidly
developing German chemical industry. He noticed that some stains
could be specific for certain microbes but not to others. Ehrlich rea-
soned that chemical compounds could be synthesized in a way that
it would be possible ‘‘to exert their full action exclusively on the
parasite harboured within the organism” (http://pubs.acs.
org/cen/coverstory/83/8325/8325salvarsan.html). Based on this
idea, in 1904, he initiated a large-scale and systematic screening
program for a drug active against syphilis, the disease that had
grown to the epidemic levels in the USA and Europe and was
hardly curable at the time. The mainstream treatment for this
sexually transmitted disease, which is caused by the spirochete
Treponema pallidium, involved administration of mercury chloride
along with other inorganic mercury salts. Due to the extreme
toxicity of mercury compounds, the treatment had severe side
effects and, yet, poor efficacy. Another type of treatment included
arsenic and inorganic arsenical compounds, but the toxicity and
low efficiency remained an issue with this treatment as well.
A less toxic organic arsenical drug, named Atoxyl, was synthe-
sized by Antoine Béchamp in 1859 [47,214], initially for the treat-
ment of African sleeping sickness. This drug attracted the attention
of Paul Ehrlich and Alfred Bertheim, an organic chemist working

http://dx.doi.org/10.1016/j.bcp.2016.10.001
0006-2952/Ó 2016 Published by Elsevier Inc.

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2 R. Aminov / Biochemical Pharmacology xxx (2016) xxx–xxx
with him. They correctly identified the chemical structure of this
compound as aminophenyl arsenic acid, thus opening the possibil-
ity of synthetizing various derivatives in the search for a more effi-
cient and less toxic therapeutic agent. They synthesized hundreds
of arsenobenzene compounds, and the arsphenamine derivative,
the sixth compound in the 600th series (i.e. compound 606), was
synthesized in 1907. Although initially aimed at the treatment of
African sleeping sickness, the drug appeared to be ineffective at
it, but, in 1909, Ehrlich and Bertheim, together with bacteriologist
Sahachiro Hata, established the efficiency of this compound in the
treatment of syphilis-infected rabbits. In subsequent limited trials
in humans, the drug demonstrated significant capacity for the
treatment of patients with this venereal disease [72]. This process
of systematic synthesis and activity check is considered to be the
beginning of the modern chemotherapeutic era (Stefan and
[213]. Almost all further developments in modern pharmaceutical
research followed this route, with systematic chemical modifica-
tions of a lead compound to improve its biological activity and les-
sen the side effects.
Despite the problems associated with its stability and storage,
as well as a rather tedious injection procedure and side effects,
the drug, marketed by Hoechst under the trade name Salvarsan,
was a great success and, together with a more soluble and less
toxic Neosalvarsan, enjoyed the status of the most frequently pre-
scribed drug until its replacement by penicillin in the 1940s [148].
Remarkably, the mode of action of this hundred-year-old drug is
still unknown, and the controversy about its chemical structure
was solved only in 2005 [142]. Other derivatives of the lead com-
pound, arsanilic acid, however, have been in a much more pro-
longed use as feed additives in poultry and swine. The U.S. Food
and Drug Administration (FDA) announced the complete with-
drawal of arsenic-based drugs for use in food-producing animals
only by the end of 2015 [83].
Presently, syphilis infections are successfully managed by peni-
cillin drugs, in particular by intramuscular injection of benzathine
benzylpenicillin, which allows reaching a prolonged antibiotic
exposure over a two- to four-week period after a single dose deliv-
ery. Patients with severe allergy to penicillin can be treated with
tetracycline or doxycycline. The availability of very efficient thera-
pies resulted in a substantial drop of mortality due to syphilis, from
202,000 in 1990 to 113,000 in 2010 [143]. Still, the number of new
infections remains relatively high, with 315,000 cases reported in
2013 [61].
3. b-Lactams
Discovered serendipitously in 1928 by Alexander Fleming [86],
penicillin did not immediately take off as a clinically useful antibi-
otic. This was hindered by many drawbacks, such as low yield,
instability, purification and other problems. In fact, military actions
in the 1940s helped to develop it into a valuable treatment of infec-
tions, with a considerable production for the treatment of sick and
wounded soldiers in the U.S. and Allies’ military forces. Thereafter,
penicillin became a widely used antibiotic for a broad range of pre-
viously untreatable infectious diseases, with a wider range of tar-
gets and fewer side effects than sulpha drugs (see the next section).
Although the antibacterial properties of mould had been known
from ancient times, and researchers before him had come upon
similar observations regarding the antimicrobial activity of Penicil-
lium fungi from time to time (e.g., Vincenzo Tiberio, see [46]), it
was Alexander Fleming’s firm faith in the idea and his impressive
determination that made the difference. For more than a decade
after his initial observation, he tried hard to involve chemists in
resolving the problems of purification and stability of the active
compound, supplying the producer strain to every request. And
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finally, in 1940, an Oxford team, led by Howard Florey and Ernest
Chain, published a paper describing the purification procedure for
penicillin in quantities sufficient for clinical testing [53]. The fol-
lowing refinements and optimizations of the original procedure,
isolation of more efficient penicillin producer strains, and opti-
mization of the strain fermentation procedure eventually led to
the mass production and distribution of penicillin in 1945 [171].
The screening procedures in the discovery of Salvarsan and
Prontosil required testing of many compounds using the animal
models of human disease. The screening method of Alexander
Fleming used inhibition zones in lawns of pathogenic bacteria on
the surface of agar-medium plates and, thus, required much less
time and resources. At least in the initial stages of screening, before
testing in animal disease models, the approach made it possible to
reasonably inexpensively test a much larger range of compounds
with a potential antimicrobial activity. This method became widely
used in mass screenings for antibiotic-producing microorganisms
by many researchers in academia and industry during the antibi-
otic discovery programmes.
Identification of 6-aminopenicillanic acid as the core of peni-
cillin by scientists of Beecham Research Laboratories in the UK
[30] allowed the synthesis and production of numerous semisyn-
thetic penicillins. The main developments included the
penicillinase-resistant penicillins, such as methicillin, oxacillin,
and nafcillin; followed by the derivatives active against Gram-
negative bacteria: the aminopenicillins (ampicillin, amoxicillin,
and bacampicillin), the carboxypenicillins (carbenicillin and ticar-
cillin), and the ureidopenicillins (mezlocillin, azlocillin, and piper-
acillin) [242]. Further developments to overcome resistance and
extend the range of targeted organisms led to the combination of
a b-lactamase inhibitor (clavulanic acid, sulbactam, or tazobactam)
and an aminopenicillin, ticarcillin, or piperacillin [242]. Although
unified under the umbrella of the b-lactam structure, this group
of antibiotics is sometimes separated into the penicillin, cephalos-
porin, and carbapenem classes. These are the most frequently pre-
scribed broad-spectrum antibiotics in outpatient care [136,202],
and, as such, may have contributed to a significant problem of
resistance towards b-lactams among pathogenic bacteria [39].
Alexander Fleming was also among the first who cautioned
about the potential resistance to penicillin if used in too little dozes
or for a too short period during treatment. Even before the exten-
sive use of penicillin, some observations suggested that bacteria
could destroy it by enzymatic degradation [1]. The outlook, how-
ever, was optimistic, largely based on the previous experience with
arsenic drugs. One of the earlier studies of possible resistance
emergence under laboratory conditions concluded that: ‘‘Syphilis
has now been treated with arsenicals for about 40 years without
any indications of an increased incidence of arsenic-resistant infec-
tions, and this work gives grounds for hoping that the widespread
use of penicillin will equally not result in an increasing incidence of
infections resistant to penicillin” [189]. Surprisingly, this is still
true for syphilis infections [52], the first line of treatment for which
is benzathine benzylpenicillin, but not for many other pathogenic
bacteria, including the Enterobacteriaceae, which have become
resistant not only to the original penicillin but also to semi-
synthetic penicillins, cephalosporins, and newer carbapenems
[130].
The rise of ESKAPE pathogens (Enterococcus faecium, Staphylo-
coccus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseu-
domonas aeruginosa, and Enterobacter spp.) [185,39] represents an
especially worrying trend. Although the majority of these infec-
tions were seemingly under control in the past, this equilibrium
in the arms race between humans and pathogens appeared to be
fragile. During the almost four billion years of evolution the micro-
bial world has accumulated an enormous diversity of metabolic
and protective mechanisms than can be mobilized in response to
 R. Aminov / Biochemical Pharmacology xxx (2016) xxx–xxx
a strong selection, including the pressure of antibiotics [6,7].
Despite being obstructed by the growing resistance problem, the
b-lactam antimicrobials remain the most widely prescribed anti-
infective agents due to their safety, efficacy, and availability
[136,202]. Strategies for the further development of this class of
antimicrobials may include the novel broad-spectrum b-
lactamase inhibitors that work against many problematic b-
lactamases such as cephalosporinases and carbapenemases [49].
This could also be the combination of two non-b-lactam families
of b-lactamase inhibitors, diazabicyclooctanes and boronic acids,
with novel or existing b-lactam antibiotics [119]. Besides, the con-
jugation of b-lactams to siderophores may allow drug entry, via
bacterial iron transport systems, into the Gram-negative bacterial
pathogens that are intrinsically resistant due to restricted porin
entry and drug efflux [119].
Another biological activity of b-lactams, not related to the killing
of bacteria, has been discovered during a large-scale screening of
the FDA-approved drugs for modulating the activity of the gluta-
mate transporter subtype 1 [192]. Glutamate is a principal excita-
tory neurotransmitter in the brain involved in memory and
learning processes [203]. A number of investigations have
suggested that ceftriaxone, which increases the expression of
glutamate transporter, displays potent neuroprotective and
immunomodulatory effects, and also could be a valuable candidate
for the treatment of alcohol and other drug dependencies due to its
capability of normalizing glutamate transmission, which is affected
in addiction [10]. Thus, the use of b-lactams that have been already
approved for the treatment of infectious diseases could be extended
to the therapy of other, non-infectious, diseases and conditions.
4. Sulphonamides
The systematic screening approach suggested by Paul Ehrlich
was then followed by others in the search for chemotherapy of
other infectious diseases. In particular, the first class of antimicro-
bials that went into the truly large-scale production was the group
of sulpha drugs. In the late 1920s and early 1930s, the German
chemical industry was experiencing a dramatic increase in the
number of newly synthesized compounds that were available for
testing, especially dye compounds, due to a common assumption
at the time that dyes, which bind specifically to bacteria and para-
sites, might then exert lethal effects on them.
In the laboratories of Bayer AG, hundreds of compounds were
synthesized and tested before coming across the compound called
sulphonamidochrysoidine (KI-730, commercial name Prontosil). It
was synthesized by Bayer chemists Josef Klarer and Fritz Mietzsch
and tested by Gerhard Domagk for antibacterial activity in several
animal disease models [69]. It appeared to be particularly effective
against streptococcal infections, while less efficient against other
cocci. Prontosil itself, however, appeared to be a precursor for the
active drug, and only the active part of it, sulphanilamide, was
actually responsible for the antibacterial activity [224]. It was not
patentable, since sulphanilamide patent had already expired, and
these compounds had been in use in the dye industry for some
years. As sulphanilamide was cheap to produce and off patent,
and the sulphanilamide moiety was easy to modify, many compa-
nies subsequently started mass production of sulphonamide
derivatives. Some of the preparations, however, included diethy-
lene glycol resulting in the death of more than 100 patients, which
enforced the introduction of a legislative framework, with a set of
laws called the United States Federal Food, Drug, and Cosmetic Act,
in 1938 (http://www.fda.gov/RegulatoryInformation/Legislation/
FederalFoodDrugandCosmeticActFDCAct/default.htm).
A recent study has evaluated the effect of the introduction of
sulpha drugs, which, between 1937 and 1943, led to a 24–36%
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3
decline in maternal mortality, a 17–32% decline in pneumonia
mortality, and a 52–65% decline in scarlet fever mortality [198].
Overall, sulpha drugs reduced mortality by 2–3 per cent and
increased life expectancy by 0.4–0.7 years. Presently, sulpha drugs
are mainly used to treat urinary tract infections and as a supportive
therapy in HIV/AIDS patients. Besides their antibacterial activity,
exerted via the competitive inhibition of the bacterial enzyme
dihydropteroate synthase, other clinical applications of sulphona-
mides include their use as anti-diabetics, diuretics, anticonvul-
sants, and antiretrovirals.
The legacy of this oldest mass-produced antimicrobial class in a
poorly regulated market is possibly reflected in one of the most
broadly disseminated cases of drug resistance, i.e. sulpha drug
resistance, which is almost universally linked with class 1 inte-
grons. Mobile genetic elements (MGEs) have been instrumental
in the rapid dissemination of antimicrobial resistance genes [8].
Moreover, once the sulpha drug resistance is established on an
MGE, it may be difficult to eliminate, because the resulting con-
struct confers a fitness advantage to the host even in the absence
of antibiotic selection [75]. Despite this, many continuously modi-
fied derivatives of this oldest class of synthetic antibiotics are still a
viable option for therapy, while the action of and resistance to sul-
phanilamides is one of the best examples of the arms race between
humans and microbes.
5. Polypeptides
It was independently discovered at the end of the 1930s and the
beginning of the 1940s that various strains of the soil bacterium
Brevibacillus brevis (formerly Bacillus brevis) produced substances
inhibiting a range of pathogenic bacteria and even fungi. This spe-
cies appeared to be producing a variety of linear and cyclic pep-
tides using nonribosomal protein synthetases [125]. Tyrothricin
isolated by René Dubos, an American microbiologist of French ori-
gin, in 1939, appeared to be a mix of cyclic and linear polypeptides
with antimicrobial activity. Its principal component is tyrocidine,
which is also a mixture of cyclic decapeptides. The nonribosomal
biosynthesis of tyrocidine is via an enzymatic assembly consisting
of 3 peptide synthetase proteins, TycA, TycB, and TycC, which con-
tain 10 modules [191]. Another cyclic polypeptide, from another
strain of B. brevis, gramicidin S (S stands for Soviet), was reported
in 1944 [92]. Other gramicidins, A, B, and C, as well as the mix of
these three called gramicidin D, are the linear pentadecapeptides
[48]. The structures of gramicidins and tyrocidines were unknown
at the time, thus a cyclic polypeptide was called gramicidin S,
while a more appropriate name would be tyrocidine S. All grami-
cidins and tyrocidines belong to the group of polypeptide antibiotic
compounds, which also include microcystin, bacitracin, and others.
Some of them, such as the amanitins and phallotoxins, are synthe-
sized ribosomally by various species of mushrooms, and can be
extremely toxic [98].
The use of gramicidins and other polypeptides, however, is lim-
ited to topical applications. The mechanism of action of these
antimicrobials is as follows: they act as channels and increase the
permeability of the bacterial cell membrane when incorporated,
thus destroying the ion gradient between the cytoplasm and the
extracellular environment [227,179]. In animals and humans, this
activity, at concentrations lower than needed to achieve the bacte-
rial killing effect, induces hemolysis. Thus, topical applications
require the skin or mucosa surface to be intact to prevent systemic
entry. Other polypeptide antibiotics also display substantial side
effects and are thus mostly used as topical applications. In excep-
tional cases, however, they can be used systemically as last resort
antibiotics when other options are exhausted, for instance in the
case of resistance or contraindications such as allergy [18].
4 R. Aminov / Biochemical Pharmacology xxx (2016) xxx–xxx
6. Aminoglycosides
In 1943, Selman Abraham Waksman headed a research team at
Rutgers University in the search for new antibiotics [235]. This
effort was fuelled by the success of penicillin that was discovered
in 1928 but did not evolve into a useful treatment until the
1940s. The same year, his student Albert Schatz isolated two
strains of Streptomyces active against tubercle bacillus and Gram-
negative bacteria resistant to penicillin and purified the active
compound, streptomycin. The authorship issue in streptomycin
discovery, however, was surrounded by considerable controversies
[233,133,120,234]. Clinical trials in the following year demon-
strated that streptomycin is effective against infectious diseases
caused by Gram-negative bacteria and Mycobacterium tuberculosis.
Despite the toxicity and an already present resistance problem, the
drug soon became the cornerstone for multidrug therapies of
tuberculosis.
Following the discovery and introduction of streptomycin and
other antibiotics into clinical practice, the mortality rates due to
tuberculosis have dramatically fallen. In the USA, for example,
the mortality rate decreased more than fourfold in a decade (from
1945 to 1955), from 39.9 deaths per 100,000 population to 9.1 [96].
Until the emergence of multidrug-resistant (MDR) M. tuberculosis
strains, the prevailing outlook was extremely confident, as
expressed by the words of the streptomycin discoverer: ‘‘the final
chapter of the battle against tuberculosis appears to be at hand”
[235].
Despite some successes in the treatment of tuberculosis, which
resulted in the drop of TB death rate by 47% between 1990 and
2015, the situation is deteriorating. In 1991, an MDR strain of M.
tuberculosis (strain W) was isolated in the USA, which was resistant
to isoniazid, rifampin, ethambutol, streptomycin, kanamycin,
ethionamide, and rifabutin [175]. According to WHO Fact Sheet N
°104, 9.6 million people fell ill with TB and 1.5 million died from
the disease in 2014 (http://www.who.int/mediacentre/factsheets/
fs104/en/). The rise of infections caused by MDR M. tuberculosis
strains that resist the first-line therapy with isoniazid and rifampi-
cin poses a major problem restricting the available therapeutic
choices. The situation is further aggravated by the emergence of
extensively drug-resistant tuberculosis (XDR-TB), which, in addi-
tion, displays resistance to fluoroquinolones (such as levofloxacin
or moxifloxacin) and to at least one of the three injectable
second-line drugs (amikacin, capreomycin, or kanamycin) (http://
www.who.int/entity/tb/areas-of-work/drug-resistant-tb/xdr-tb-
faq/en/index.html).
As early as in 2007, two tuberculosis cases that resisted all
available drugs and long-term (5–8 years) treatments and eventu-
ally resulted in the death of both patients were reported in Italy
[154]. In 2009, the emergence of new forms of resistant M. tubercu-
losis strains, totally drug-resistant (TDR), was also documented in
Iran [231]. These strains were resistant to all first- and second-
line drugs tested (isoniazid, rifampicin, streptomycin, ethambutol,
pyrazinamide, ethionamide, para-aminosalicylic acid, cycloserine,
ofloxacin, amikacin, ciprofloxacin, capreomycin, and kanamycin).
TDR tuberculosis cases have been also described in India and South
Africa [226,123].
Although presently relatively rare, these cases demand immedi-
ate actions geared towards the rapid identification and contain-
ment of these dangerous strains to prevent further outbreaks of
untreatable TB [232]. Secondly, new antibiotics that are effective
against these extremely problematic infections have to be urgently
sought. Bedaquiline is the first new medicine for TB in more than
forty years and received a fast-track approval by the FDA for use
only in cases of MDR and TDR tuberculosis that resist the first and
second lines of treatment [81]. Unlike other quinolones, the molec-
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ular target of this antibiotic is mycobacterial ATP synthase, not DNA
gyrase. Targeting energy metabolism may thus represent a new,
promising approach for antibacterial drug discovery [13,126]. There
are a number of compounds at various stages of clinical and preclin-
ical trials for the treatment of TB, especially its drug-resistant forms
(http://www.newtbdrugs.org/pipeline.php).
Aminoglycosides were extensively used in the early days of
antimicrobial chemotherapy but were largely replaced in the
1980s with more efficient antimicrobials, with lesser side effects,
such as cephalosporins, carbapenems, and fluoroquinolones
[127]. There is, however, a renewed interest in aminoglycosides
due to the ever-increasing problem of antibiotic resistance. In par-
ticular, gentamicin is still widely used in hospital settings for treat-
ment of serious infections [131]. Amikacin is commonly used in
intensive care units for the treatment of patients with life-
threatening Gram-negative infections [150]. Aminoglycosides dis-
play synergistic activities in combination with other antibiotic
classes, while the safety and efficacy issues can be potentially
solved via PK/PD-based optimised therapy regimens.
7. Tetracyclines
The first antibiotic of this class, chlortetracycline, was discov-
ered in 1945 by Benjamin Minge Duggar under the supervision
of Yellapragada Subbarow at Lederle Laboratory Division of Amer-
ican Cyanamid Company [71]. The antibiotic-producing soil bac-
terium was named Streptomyces aureofaciens, and the antibiotic
purified from it was marketed under the trade name Aureomycin,
to reflect the golden colour of both the producer colonies and the
product purified. Aureomycin was almost immediately examined
in the treatments of various human infections, and the first pre-
scriptions were issued within a timeframe that is almost unimag-
inable for the tempo of current drug development. The clinical
evaluations demonstrated a broad clinical applicability of the drug,
estimated to be equal in value to penicillin [241].
The interesting twist in the tetracycline story is that the animal
growth promoting properties of antibiotics were for the first time
demonstrated namely with this antibiotic. Colleagues of Benjamin
Minge Duggar at Lederle Laboratory Division, animal nutritionist
Robert Stokstad and biochemist Thomas Jukes, accidentally came
across the growth promoting effects of the biomass of S. aureofa-
ciens, left after the fermentation and extraction of Aureomycin,
on chickens. This discovery occurred during their search for
sources of vitamin B-12, and the debris of S. aureofaciens contained
a substantial amount of it. It appeared, however, that the growth
promoting property was not due to the vitamin but because of
the low residual antibiotic left in the producer biomass after
antibiotic extraction. Ensuing the discovery, American Cyanamid
Company swiftly initiated the development of antibiotic feed addi-
tives for growth promotion of food animals, and this exemplar was
promptly followed by many other companies and countries around
the globe. It is highly likely that the extremely rapid onset and glo-
bal dissemination of tetracycline resistance among pathogens was
(and is) mainly due to the massive use of tetracyclines by the food
animal industry. It took a considerable amount of time and efforts
to reveal this link, and the corresponding legislative measures to
limit and ban the use of growth-promoting antibiotics were first
implemented in the European Union (EU) countries. Sweden pro-
hibited them in 1986, while other EU countries banned specific
antibiotics in feedstuffs prior to January 1, 2006, when all these
antibiotics were deleted from the Community Register of autho-
rized feed additives [76,50].
In a parallel drug discovery programme, which was a collabora-
tive effort between Pfizer and Harvard University, the research
 R. Aminov / Biochemical Pharmacology xxx (2016) xxx–xxx
team discovered and resolved the chemical structure of another
tetracycline antibiotic, oxytetracycline (trade named Terramycin)
[109]. With the determination of the chemical structure of other
tetracyclines, this group of antibiotics is currently defined as: ‘‘A
subclass of polyketides having an octahydrotetracene-2-carboxa
mide skeleton, substituted with many hydroxy and other groups”
[113]. Resolving the chemical structure of natural tetracyclines laid
the foundation for the development of the second-generation
tetracyclines, such as doxycycline and minocycline, to combat
the ever-growing resistance problem [163].
Another interesting aspect of tetracyclines is that there are indi-
cations of their ancient consumption well before their discovery in
the modern era. The traces of tetracycline have been found in
human skeletal remains from ancient Sudanese Nubia dating back
to 350–550 CE [28]. The efficient incorporation and binding of
tetracycline to the mineralizing surface of the bone is well known
in clinical research and histomorphometry applications. It is a
standard method for determining the rate of bone formation in
all bone compartments, including cancellous, endocortical, intra-
cortical, and periosteal bone [139]. The presence of tetracycline
incorporated in bones of ancient Sudanese Nubians is only explica-
ble if there was exposure to tetracycline-containing materials in
the diet of these ancient people. The second case of tetracycline
incorporation in bones of Sudanese Nubians is documented for
the remains from the medieval period (550–1450 CE) [110].
Although there have been some doubts regarding the identity of
the fluorescent compound(s) in the ancient bones, the results of
mass spectroscopic characterization conclusively identified them
as tetracyclines [162].
Another example of ancient tetracycline exposure came from a
histological study of samples taken from the femoral midshafts of
the late Roman period skeletons from the Dakhleh Oasis, Egypt
[62]. The samples demonstrated discrete fluorochrome labelling
consistent with the presence of tetracycline, thus suggesting its
intake with the diet in the late Roman period [62]. The hypothe-
sized intake of tetracycline may potentially have had a protective
effect because the rate of infectious diseases documented in the
Sudanese Nubian population was low, and no traces of bone infec-
tion were detected in the samples from the Dakhleh Oasis [15,62].
There was no correlation, however, between the exposure to low
concentrations of tetracycline and disease incidence in the medie-
val population of Sudanese Nubia [110].
As mentioned before, the extensive use of tetracyclines in clin-
ical medicine and in production of food animals started from the
1950s. In 2013, the leading antibiotics by use in food animals in
the USA were tetracyclines (6,514,779 kg of active ingredient
annually), which accounted for 71% of all antibiotics sold for use
in food-producing animals [84]. Tetracyclines administered via
medicated feed accounted for the majority of domestic sales and
distribution of medically important antimicrobials approved for
use in food-producing animals, and they were also the leading
antibiotics for administration via drinking water [84]. Besides,
the non-clinical use of tetracyclines was extended to aquaculture
and horticulture [57]. The clinical use of the first-generation tetra-
cyclines, however, progressively decreased due to the widespread
resistance towards this antibiotic class. The most common mecha-
nisms of resistance are the efflux of tetracycline from the cell and
ribosomal protection, where tetracycline is prevented from bind-
ing to the ribosome because of the synthesis of alternative elonga-
tion factors [57]. The less conspicuous mechanisms of tetracycline
resistance included the enzymatic degradation of tetracycline
[209] and, presumably, a metabolic mechanism protecting against
the entry of the antibiotic into the cell [117]. The wide dissemina-
tion of antibiotic resistance genes is facilitated by their location on
MGEs, allowing an almost indiscriminate exchange among a
variety of taxonomic entities [8].
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5
The rapid expansion of tetracycline resistance among the
human and animal pathogens prompted the development of the
second-generation tetracyclines such as minocycline (available
from 1966 [184]) and doxycycline (available from 1967 [60]). They
are used to treat many different infectious diseases, such as urinary
and intestinal tract infections, respiratory infections, skin infec-
tions, acne, gonorrhoea, tick fever, chlamydia, eye infections, peri-
odontitis, and others. Besides the antibacterial effects, they also
display other potent activities directed towards the eukaryotic cell
targets [10]. In particular, minocycline displays strong anti-
inflammatory, neuroprotective, anti-proteolytic, and anti-
apoptotic properties, as well as inhibits angiogenesis and meta-
static growth [91]. In addition, it displays antioxidant activity, inhi-
bits several enzyme activities, and modulates immune cell
activation and proliferation [10].
In June 2005, tigecycline, the first representative of the third-
generation tetracyclines (also called glycylcyclines), was approved
by the FDA [190]. It is administered intravenously to treat compli-
cated skin and intra-abdominal infections, as well as respiratory
infections. It is active against many MDR pathogens including S.
aureus, A. baumannii, K. pneumoniae, and Escherichia coli. After a
decade of clinical use, tigecycline remains relatively active towards
infections caused by the Enterobacteriaceae, with resistance rates
largely <10% in most of the wide-scale surveillance studies per-
formed [248]. Among the mechanisms that may confer resistance
to tigecycline, RND-type transporters, such as the AcrAB efflux
pump, may play a major role. The extensive dissemination of the
tet(X) gene, which confers resistance to all tetracyclines, including
tigecycline, to pathogenic microbiota may also represent a signifi-
cant problem in controlling resistance to this antibiotic [11].
8. Amphenicols
Chronologically, the next antibiotic in the pipeline of the antibi-
otic drug discovery programmes was chloramphenicol, which was
discovered and isolated from Streptomyces venezuelae by David
Gottlieb in 1947. It belongs to the class of amphenicols, with a
phenylpropanoid structure. Although it was initially isolated from
a natural source, chemical synthesis appeared to be more advanta-
geous, and chloramphenicol became the first antibiotic produced
synthetically on an industrial scale [68]. Chloramphenicol easily
crosses the haematoencephalic barrier and, in some cases, could
be the drug of choice for the treatment of bacterial meningitis
caused by Neisseria meningitidis, Streptococcus pneumoniae, and
Haemophilus influenza, especially in patients with an allergy to b-
lactams or in patients with other serious infections when alterna-
tive medications are contraindicated or inefficient [73]. The main
disadvantage of the antibiotic is in its side effects, which are quite
common after a prolonged use, and may include haematological
disorders such as aplastic anaemia, bone marrow suppression,
and leukaemia. It may cause neurotoxicity and Grey syndrome in
infants because of the accumulation of toxic chloramphenicol
metabolites in patients of this age group [45].
To circumvent the toxicity and side effect problems, a number
of other amphenicol derivatives have been synthesized [68], and
some of them, such as thiamphenicol, azidamfenicol, and florfeni-
col, have even entered into clinical and veterinary practice. The rel-
atively simple molecule of chloramphenicol opened the possibility
of constructing hybrid antibiotics, where the segments of two
drugs are covalently connected into one molecule [68]. Besides
antimicrobial activities, this class of drugs may find potential
applications in cancer therapy [68].
The most frequently encountered mechanism of resistance
towards chloramphenicol is its enzymatic inactivation by acetyla-
tion, via different types of chloramphenicol acetyltransferases
6 R. Aminov / Biochemical Pharmacology xxx (2016) xxx–xxx
[197]. Less frequent are the efflux of chloramphenicol, its inactiva-
tion by phosphotransferases, target mutations, and permeability
barriers.
9. Lipopeptides
The structure of this class of antimicrobials includes a cyclic
peptide with a hydrophobic tail. Of significant clinical relevance
is colistin (also known as polymyxin E), a polypeptide antibiotic
produced by certain strains of Paenibacillus polymyxa (formerly
Bacillus polymyxa var. colistinus). It was discovered in Japan in
1947 and entered the clinical practice in 1949 [215]. It fell out of
favour, however, because of a variety of adverse effects, such as
nephrotoxicity, ototoxicity, and neuromuscular blockade, and
when other, less toxic, antimicrobials became available [249]. With
the emergence and dissemination of Gram-negative bacterial
pathogens that are resistant to the mainstream treatment with
the aminoglycosides, b-lactams, and quinolones, there is a renewed
interest in the use of colistin. It can be used as a last resort antibi-
otic against serious and difficult-to-treat infections such as those
caused by multidrug-resistant P. aeruginosa, K. pneumoniae, and
A. baumannii [79]. Multidrug-resistant isolates of the Enterobacte-
riaceae expressing the novel NDM-1 metallo-b-lactamase still
remain susceptible to colistin [130].
Colistin targets the bacterial cell membrane of Gram-negative
bacteria. It initially associates with the anionic lipopolysaccharide
(LPS) molecules in the outer membrane of Gram-negative bacteria
and displaces magnesium and calcium, which stabilize the nega-
tively charged LPS molecules [78]. This results in a local distur-
bance of the outer membrane, with increased permeability,
leakage of the cell content, and, eventually, cell death. Although
presently rare, resistance to colistin is emerging. It is encoded on
a plasmid with a very high conjugative transfer frequency and a
potential for rapid dissemination to key pathogenic species of the
Enterobacteriaceae [140]. The authors suggest that one of the main
causes of the emerging resistance could be its large-scale use in
agriculture. Another worrying finding is that colistin therapy may
increase pathogen resistance to host cationic antimicrobials
[161]. Colistin selection for pathogen resistance against the first
line of host’s innate immunity defence may potentially facilitate
the infection process and thus increase the infection rates.
Another cyclic lipopeptide antibiotic, daptomycin, is produced
by Streptomyces roseosporus [218]. It was discovered by researchers
at Eli Lilly and Company in early 1980s but did not enter the clin-
ical practice until 2003 [212]. It is active only against Gram-
positive bacteria, including vancomycin-resistant enterococci
(VRE) and methicillin-resistant S. aureus (MRSA). The mechanism
of action includes primarily targeting bacterial cell membranes
leading to the mislocalization of essential cell division proteins
and causing severe cell wall and membrane defects, with an even-
tual breach in the cell membrane integrity and cell death [176].
The antibiotic is well tolerated, with the frequency and distribution
of adverse effects similar to comparator drugs [194]. Resistance to
daptomycin remains rare. In S. aureus, it is the result of incremental
accumulation of point mutations in genes encoding a lysylphos-
phatidylglycerol synthetase, a histidine kinase, and RpoB and RpoC
subunits of RNA polymerase [89]. There is a good potential for the
development of various daptomycin derivatives using a biosyn-
thetic engineering approach [23].
A group of lipopeptides called echinocandins display
potent antifungal activities [65]. They noncompetitively inhibit
b-(1,3)-D-glucan synthase, an essential enzyme complex for the
synthesis of glucan in the fungal cell wall [156]. They were discov-
ered in 1970s during extensive screening programmes for antifun-
gals with a broad-spectrum activity against the species of Candida.
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Although the natural products appeared to be toxic, the synthetic
modifications allowed lowering the toxicity, and the approved
drugs among the semi-synthetic echinocandins include caspo-
fungin, micafungin, and anidulafungin [156]. In a recent report
by the Centers for Disease Control and Prevention regarding the
microorganisms with a serious threat level, the only fungal patho-
gen among the 12 most serious threats is a fluconazole-resistant
Candida [51]. Thus the echinocandins serve as a valuable first-
line treatment option against these serious fungal infections. Resis-
tance to the echinocandins is rare, essentially limited to the case
studies with the resistance emerging during the treatment [77].
10. Macrolides
The first antibiotic of the macrolide class, pikromycin, was iso-
lated from Streptomyces venezuelae by Brockmann and Henkel in
1950 [42,43]. It has not advanced to clinical use but still remains
an important precursor for the synthesis of other macrolides and
derivatives [121]. The first commercially successful macrolide, ery-
thromycin (also known as Ilosone or Ilotycin to reflect the soil sam-
ple collection place in the Iloilo region in the Philippines), was
discovered by the team of scientists led by J. M. McGuire at Eli Lilly
[153]. Acting within the antibiotic discovery programme there, the
team tested many soil samples, including the one sent in 1949 by
Abelardo Aguilar, a Filipino scientist employed by the company.
The genome sequence of the erythromycin producer, Saccha-
ropolyspora erythraea (formerly Streptomyces erythraeus), was pub-
lished in 2007 [167].
Structurally, the natural macrolides consist of a large macro-
cyclic lactone ring, which is typically 14-, 15-, or 16-membered.
One or more deoxy sugars may be attached to the lactone ring.
Their natural synthesis is performed by polyketide synthases,
which is a family of multi-domain enzymes or enzyme complexes
that can be found in the representatives of bacterial and eukaryotic
domains [118,115]. Besides the macrolide biosynthesis, polyketide
synthases are also involved in the biosynthesis of many other bio-
logically active secondary metabolites. These include a broad range
of compounds covering other antibiotic classes such as tetracycli-
nes, as well as immunosuppressants/immunomodulators, and
anticholesterol and anticancer drugs [124]. In terms of infection
control, the macrolides are possibly the second most prescribed
antibiotic class after the b-lactams, targeting a similarly broad
range of bacterial pathogens, although with a lesser efficiency
against Gram-negative bacteria. The obvious advantage of the
macrolides over the b-lactams is in the activity against bacteria
lacking the cell wall target such as the mycoplasmas. Macrolides
are also among the first-line treatment options for patients with
penicillin allergy. The subgroup of macrolides, polyene antimy-
cotics, consists of antibiotics active against fungal infections, and
these include amphotericin B, nystatin, and others [99].
Various modifications of natural macrolides have been per-
formed to improve the pharmacokinetic properties of antibiotics
in this class, such as the use of the azalide scaffold [112,216]. This
approach was initially implemented in the synthesis of 9-dihydro-
9-deoxo-9a-methyl-9a-aza-9a-homoerythromycin A (azithromy-
cin) by the Croatian pharmaceutical company Pliva in 1980 [95].
The antibiotic displays outstanding pharmacokinetic properties,
including the lack of inhibition of cytochrome P450 3A4 [12,159].
It was the most prescribed antibiotic for outpatients in the US in
2010 [107]. With other macrolides, this group of antibiotics is
among the most frequently prescribed anti-infective drugs in out-
patient care [136,202].
Further efforts to improve the antibacterial activities of macro-
lides have been focused on increasing the affinity to the target and
the capability to bind to a larger number of sites on the ribosome
 R. Aminov / Biochemical Pharmacology xxx (2016) xxx–xxx
target. These works have led to the development of ketolides and
fluoroketolides. The first and the only approved ketolide drug, teli-
thromycin, was developed by the French pharmaceutical company
Hoechst Marion Roussel (later a subsidiary of Sanofi-Aventis and
then Sanofi) and approved by the European Commission in 2001
and by the FDA in 2004. The most important modifications of the
precursor erythromycin molecule included the removal of the neu-
tral sugar L-cladinose from position 3 of the macrolide ring and the
subsequent oxidation of the 3-hydroxyl to a 3-keto functional
group, thus also giving the ketolides name for this group of drugs
[196]. Other modifications included the addition of a carbamate
ring in the lactone ring, attachment of an alkyl-aryl moiety to the
carbamate ring, and methylation of carbon at position 6. The affin-
ity of the resulting compound, telithromycin, to the 50S subunit of
the ribosome is more than by an order of magnitude higher than
that of erythromycin. Besides, telithromycin displays a strong
binding capability to two domains in the 23S RNA molecule, while
a strong binding of older macrolides is limited only to one domain,
with a weak binding to the second domain. The significant advan-
tage of this design is that telithromycin is also active against bac-
teria resistant to older macrolides. Resistance to macrolides is
frequently due to the dimethylation of the adenine residue
A2058 in the 23S rRNA molecule, which protects the ribosome
against the antibiotic action [237]. But since telithromycin has
the capability to bind strongly to another site, it overcomes the
resistance conferred by this mechanism.
The only fluoroketolide drug, solithromycin (oral formulation
called Solithera), is currently undergoing the final stages of clinical
trials and has not yet been approved. With its three binding sites
on the ribosome target, it is an important improvement compared
to the ketolides [138]. It also lacks the pyridine-imidazole group
present on the side chain of telithromycin, which acts as an antag-
onist of various nicotinic acetylcholine receptors and thus causes
off-target undesirable side effects [34].
Besides the antimicrobial use, the macrolides have demon-
strated very good anti-inflammatory and pro-kinetic properties
in the treatment of various chronic respiratory diseases of non-
infectious nature. It was demonstrated, almost three decades ago,
that the long-term administration of low-dose erythromycin had
a positive effect on patients with diffuse panbronchiolitis [129].
From this point on, the use of macrolides in the therapy of chronic
respiratory diseases of non-infectious nature became one of the
mainstream options in the management of this group of diseases
[160]. Other pulmonary diseases, for which the non-antimicrobial
therapeutic effect of macrolides has been demonstrated, include
cystic fibrosis [144], asthma [93], and chronic obstructive pul-
monary disease [199]. Furthermore, the positive non-
antimicrobial therapeutic effect of macrolides has been demon-
strated in cardiovascular diseases, autoimmunity, prophylaxis of
transplant rejection, and a number of other conditions [10]. Alleg-
edly, these therapeutic effects of macrolides are due to their anti-
inflammatory properties [10].
11. Oxazolidinones
The oxazolidinones class of antimicrobials is characterised by
the presence of 2-oxazolidone in their chemical structure. There
are two groups in this class that differ in their mechanism of
antimicrobial activity. The first is represented by cycloserine ((R)-
4-amino-1,2-oxazolidin-3-one), which was initially isolated from
Streptomyces K-300 strain by Kurosawa in 1952 and named orien-
tomycin [27]. The antimicrobials isolated later from S. lavendulae, S.
orchidaceus, S. garyphalus, and other Streptomyces species appeared
to be identical in structure and were given the generic name
cycloserine or D-cycloserine. It can also be synthesized chemically
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7
[211]. The antibacterial action of D-cycloserine is mainly due to the
inhibition of D-Ala-D-Ala ligase activity, thus interfering with cell-
wall biosynthesis [180]. The drug is a second-line antibiotic used
in the treatment of tuberculosis, particularly of MDR M. tuberculo-
sis infections [250]. The recently uncovered resistance mechanism
of M. tuberculosis towards D-cycloserine involves the loss-of-
function mutations in ald (Rv2780), which encodes the L-alanine
dehydrogenase [66].
The mechanism of the antibacterial activity in the second group
of oxazolidinones involves the inhibition of protein synthesis, by
targeting an early step involving the binding of N-
formylmethionyl-tRNA to the ribosome [204]. The antibacterial
properties of compounds in this group were already known in
the 1970s, and a number of derivatives were synthesized by
DuPont Pharmaceuticals researchers as potential antimicrobials
for use in mammals [206,41]. While active in vitro, they were, how-
ever, too toxic, affecting in particular the liver, in order to be useful
in clinical applications. Finally, the oxazolidinone research pro-
gramme at Pharmacia & Upjohn (now part of Pfizer) resulted in a
relatively safe antimicrobial, linezolid [155,88], which was
approved by the FDA in 2000 and, shortly thereafter, by the corre-
sponding regulatory bodies in a number of other countries.
Linezolid is active against Gram-positive bacteria and especially
useful for the treatment of skin, pulmonary and other infections
such as those caused by MDR streptococci, VRE, and MRSA [174].
It is not clinically effective against Gram-negative pathogens as a
result of endogenous efflux activity in these organisms [141].
Although relatively safe during short-term treatments, a more pro-
longed use may result in peripheral or optical neuropathy, most
likely due to the mitochondrial toxicity of the drug [207,26]. Resis-
tance to linezolid remains low, in a survey of clinical isolated from
23 countries all streptococci were found to be susceptible, and the
resistance was rare among S. aureus (0.03%), coagulase-negative
staphylococci (0.28%), and the enterococci (0.11%, 0.55% intermedi-
ate) [116]. Other drugs in this group include tedizolid, which was
approved by the FDA in 2014 [82], and a number of other oxazo-
lidinones are currently under the various stages of development.
12. Glycopeptides
This class consists of antibiotics composed of glycosylated cyclic
or polycyclic peptides synthesized nonribosomally. The first repre-
sentative of the class, vancomycin, was discovered in 1953 by
Edmund Kornfeld and the team at Eli Lilly in the producer bac-
terium Amycolatopsis orientalis (formerly Streptomyces orientalis
and Nocardia orientalis), which was isolated from the soil sample
brought from Borneo [205,137]. Vancomycin and resistance to it
has received considerable media attention, because the drug is
not a first-line antibiotic but is reserved as a last resort option
for life-threatening conditions, such as septicemia, and compli-
cated infections of the lower respiratory tract, skin, and bones
caused by Gram-positive bacteria [38]. The emergence and dissem-
ination of VRE [14], vancomycin-intermediate S. aureus (VISA)
[108], and vancomycin-resistant S. aureus (VRSA) [54,90] may rep-
resent a significant problem for healthcare facilities such as hospi-
tals. There are suggestions that the agricultural growth-promoting
use of another glycopeptide antibiotic, avoparcin, may have con-
tributed to the wide dissemination of vancomycin resistance
[19,59,2].
The mechanisms of vancomycin action and the corresponding
resistance mechanisms are largely well understood, especially that
of the acquired resistance. The drug inhibits cell wall biosynthesis
in Gram-positive bacteria by tightly binding to the terminal dipep-
tide D-Ala-D-Ala on the end of the precursor peptide chains, thus
preventing transpeptidation and transglycosylation, which halts
8 R. Aminov / Biochemical Pharmacology xxx (2016) xxx–xxx

the cross-linking of the cell wall, and leads to cell lysis and death
[114]. Acquired resistance to vancomycin is mainly caused by the
modification in the terminal amino acid residues of the precursor
peptide. The van genes, which usually reside on MGEs, encode
the set of enzymes that alter these residues to D-Ala-D-Lac, with a
dramatic loss of the target affinity to vancomycin, which makes
the cell wall biosynthesis insensitive to the inhibitory action of
the drug [17]. Another modification of the terminal dipeptide to
D-Ala-D-Sermay also offer protection against the drug but at a
much lower level [178]. An interesting and valuable approach
has been proposed to overcome this type of resistance by reengi-
neering vancomycin to confer a dual binding capability to A-Ala-
A-Ala and A-Ala-A-Lac, with a resulting significant activity against
VanA VRE [63]. The subsequent vancomycin reengineering works
resulted in derivatives with a remarkable spectrum of extremely
potent activities against both vancomycin-sensitive and
vancomycin-resistant pathogenic bacteria [243,244,165,166].
The second natural antibiotic of this class, teicoplanin (formerly
named teichomycin) was isolated from Actinoplanes teichomyceti-
cus and described in 1978 [172,24]. Teicoplanin actually represents
a mixture of several compounds consisting of five major compo-
nents (A2-1 through A2-5), one hydrolysis component (A3-1),
and four minor components (RS-1 through RS-4) [33]. The compo-
nents from A2-1 to A2-5 contain the same teicoplanin glycopeptide
core, and they differ only by the lengths and branching of their
acyl-aliphatic side-chains. Compared to vancomycin teicoplanin
demonstrates better pharmacokinetics allowing once-daily dosing,
and it is also a safer drug, with a lower incidence of nephrotoxicity
or ototoxicity [158]. Thus teicoplanin may have pharmacoeco-
nomic advantages over vancomycin in at least of treatment of sim-
ilar Gram-positive bacterial infections [210,239]. Teicoplanin
remains active against vancomycin resistance caused by VanB
and VanC, but is not active against VanA resistant strains [173].
According to a large European survey, however, the resistance
levels among Gram-positive bacterial pathogens during 1995 were
similar towards the two antibiotics [97].
The currently approved second-generation glycopeptides
include telavancin (approved by the [80], and oritavancin and dal-
bavancin (both approved in 2014) [35]. In addition to the ‘‘classi-
cal” activity of glycopeptide, such as the inhibition of cell wall
biosynthesis, telavancin and oritavancin also disrupt bacterial
membrane integrity and increase membrane permeability, while
oritavancin also inhibits RNA synthesis [247]. The multiplicity of
targets makes them extremely potent, surpassing the potency of
vancomycin by 4- to 8-fold [122]. Another advantage of some
second-generation glycopeptides is excellent pharmacokinetics
allowing less frequent administrations such as once-daily for tela-
vancin, once-weekly for dalbavancin, and one dose per treatment
for oritavancin [228,247]. These antimicrobials are also called the
lipoglycopeptides to reflect the synthetic modifications made to
the parent glycopeptides by the addition of lipophilic tails
[247,187].
13. Streptogramins
Streptogramins have been isolated from many different species
of Streptomyces in the course of numerous antibiotic discovery pro-
grammes in many companies, so it is hard to tell which strep-
togramin was discovered first [58]. According to the available
literature, the first description of streptogramin was published by
Charney and others [55]. Among streptogramins, probably the
most known is virginiamycin, which was (and still is) used exten-
sively in food animals for growth-promoting purposes [25,246]. In
pigs, addition of virginiamycin to feed is superior compared to
chlortetracycline in terms of growth promotion (9% faster) and
feed conversion efficiency (5% more efficient) [152]. The former
is also used in fuel ethanol production to prevent and treat bacte-
rial contamination during the fermentation process [37]. Only con-
siderably later, the streptogramins, such as pristinamycin and
quinupristin/dalfopristin, started to be marketed for human con-
sumption as well [100,4]. The targeted pathogens are mainly the
strains of VRE and MRSA [64,74].
Streptogramin antibiotics are unique in the sense that the pro-
ducer strains synthetize two structurally unrelated antibiotics,
streptogramin A, which is a cyclic hybrid peptide-polyketide
macrolactone compound, and streptogramin B, which is a cyclic
depsipeptide compound [58]. The combination of these two results
in a potent synergistic antibacterial action. In particular, binding of
streptogramin A to the bacterial ribosome facilitates binding of
streptogramin B to the same target, and the synergy of actions
results in rapid bacterial cell death [67]. X-ray structural analyses
suggests that streptogramin B, which is a cyclic depsipeptide com-
pound, acts analogously to the macrolides by binding to the ribo-
somal exit tunnel and blocking it [102]. Streptogramin A binds
close to streptogramin B within the peptidyl transferase centre,
thus affecting both A- and P-site occupation by tRNA molecules.
The conformational changes of the ribosome imposed by the strep-
togramins, therefore, may be responsible for their bactericidal
activity and the post-antibiotic inhibition of protein synthesis
[102].
Although streptogramin B is a cyclic hexadepsipeptide, which is
structurally different from the macrolides and lincosamides, these
three classes of antibiotics share the similar functionality of bind-
ing to the same site on the 50S ribosomal subunit. Structural stud-
ies suggest that macrolide–lincosamide–streptogramin B classes
(MLSB) of antibiotics share a common mode of action, which is
modulated by the space available between the peptidyl transferase
centre and the drug [219]. Thus, it is not surprising that there is
overlapping resistance to these three classes of antibiotics. In par-
ticular, these are the erm genes that encode methylases, which
dimethylate the adenine residue A2058 in the 23S rRNA compo-
nent of the 50S large subunit of the bacterial ribosome [237]. The
residue is located within the conserved region of domain V, which
is a binding site for MLSB antibiotics. As a consequence, this results
in cross-resistance to all three classes of antibiotics, MLSB resis-
tance, towards macrolides, lincosamides, and depsipeptides
[135]. Chimeric streptogramin-tyrocidine antibiotics could be
potentially helpful in overcoming streptogramin resistance [157].
14. Ansamycins
A representative of this class, rifamycin (more precisely a mix of
rifamycins A, B, C, D, and E), was first obtained in 1957 by Piero
Sensi, Maria Teresa Timbal and Pinhas Margalith, while working
at Gruppo Lepetit SpA in Milan. The producer strain, named at
the time Streptomyces mediterranei, was isolated from the soil sam-
ple collected in southern France [149]. The producer strain was
renamed several times, to reflect more accurately its taxonomy
according to various taxonomic criteria and phylogeny. Thus it
went from the original naming as S. mediterranei to Nocardia
mediterranei [220], to Amycolatopsis mediterranei [134] and, finally,
to Amycolatopsis rifamycinica [20].
The rifamycins appeared to be rather unstable to purify from
the culture broth, except for Rifamycin B, which, unfortunately,
was practically inactive [200]. However, it is spontaneously oxi-
dized and hydrolysed in aqueous solutions to produce the highly
active Rifamycin S. Further chemical modifications yielded Rifamy-
cin SV, which became the first member of the ansamycins class to
enter clinical use. An additional modification yielded an improved
derivative, Rifamide, which entered the clinical practice, but was

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 R. Aminov / Biochemical Pharmacology xxx (2016) xxx–xxx
limited to intravenous use. Among further modifications that
included several hydrazones of 3-formylrifamycin SV, the hydra-
zone with N-amino-N’-methylpiperazine (rifampin or rifampicin)
appeared to be suitable for peroral use and, ensuing successful
clinical trials, was introduced into therapeutic use in 1968 [200].
Other semisynthetic derivatives include rifapentine, rifabutin,
rifalazil, and rifaximin. The latter has a poor oral bioavailability
and is used for the prevention of travellers’ diarrhoea [151]. It is
also currently investigated for the treatment of other non-
infectious pathologies of the gastrointestinal tract such as IBS
and IBD [177,195]. Rifalazil is used for the treatment of persistent
chlamydia infections [193]. But other rifamycins, including the
original drug, remain the first-line treatment for tuberculosis,
leprosy, and other mycobacterial infections, where they are usually
used in combination with other antimicrobials [201]. Other drugs
among ansamycins include antimicrobials, such as naphthomycins
[22] and streptovaricins [186], as well as an antitumor antibiotic
geldanamycin [32].
The mechanism of antimicrobial activity of rifamycins is unique
among other antibiotics in that it targets bacterial DNA-dependent
RNA polymerase, with no cross-resistance with other antibiotics
[236]. Resistance to rifamycins develops quickly; in mycobacteria
these are point mutations in the target gene, with amino acid
changes that significantly decrease the affinity of the b-subunit
to the drug [182,87]. Other mechanisms of resistance include
duplication of the target, action of RNAP-binding proteins, various
enzymatic modifications of rifamycins, and alteration of cell per-
meability [225]. Similar to quinolone resistance (see the next sec-
tion), some of the rifamycin resistance mechanisms may have the
environmental origin [225,208].
15. Quinolones
This group of antimicrobials is unique in the sense that its first
representative, nalidixic acid, was discovered during an attempt of
chloroquine synthesis [238]. After the introduction of nalidixic acid
in 1962 for the treatment of urinary tract infections, the synthesis
of other derivatives to broaden the range of targeted bacterial
pathogens resulted in tens of thousands of new compounds, few
of which have entered clinical practice and represent the currently
defined four generations of quinolones. The division into the gen-
erations is fairly arbitrary, except for the first generation, which
is represented by the nonfluorinated drugs, while all later genera-
tions are exclusively fluorinated compounds (usually fluorinated at
the C-6 or C-7 position) and, thus, are commonly called fluoro-
quinolones. The most known antimicrobial activity of quinolones
is due to the formation of a DNA gyrase-quinolone-DNA complex,
which blocks the bacterial chromosome replication leading to cell
death [106]. Besides bacterial DNA gyrase, quinolones may also
have other targets in the bacterial cell. Bedaquiline, for example,
targets energy metabolism by inactivating ATP synthase [13,126].
In addition to the antibacterial activities, the 4-quinolone scaffolds
exhibit many other pharmacological properties such as antiviral,
antitumor, antiischemic, and anxiolytic activities [3,29].
Since the synthesis and testing of fluoroquinolones were aimed
at targeting a broad range of bacteria, the approved drugs are suit-
able for the treatment of a variety of infections, with no obvious
Gram-positive vs. Gram-negative bias. They were the third in
terms of outpatient prescription frequency, after the b-lactams
and macrolides, in the period from 2000 to 2010 [136]. Within a
narrower and more recent timeframe (2007–2009), however,
ambulatory prescriptions of quinolones were the highest (25% of
antibiotics), followed by macrolides (20%), and aminopenicillins
(12%) [202]. Thus in recent years the quinolones became a pre-
ferred choice for physicians to treat respiratory and skin/mucosal
Please cite this article in press as: R. Aminov, History of antimicrobial drug discovery – Major classes and health impact, Biochem. Pharmacol. (2016),
http://dx.doi.org/10.1016/j.bcp.2016.10.001
9
conditions and urinary tract infections in outpatient care. This
trend, however, is highly undesirable because the frequent use of
these broad-spectrum antibiotics as a first-line treatment for many
infectious diseases may lead to a widespread resistance problem.
Recently the FDA issued a recommendation to restrict the use of
fluoroquinolones for treatment of uncomplicated infections so they
can ‘‘. . .be reserved for those who do not have alternative treat-
ment options” [85].
The mechanism of antimicrobial action of fluoroquinolones is
mediated via the formation of DNA gyrase-quinolone-DNA com-
plex blocking the replication process and thus leading to cell death
[106]. The mechanisms of resistance to this class of antimicrobials
are of great interest because these are completely synthetic com-
pounds. It is generally thought that one of the main contributors
of antibiotic resistance genes for dissemination to other bacteria,
including pathogens, are the producers of antibiotics, which thus
protect themselves from the lethal action of antibiotics they pro-
duce [240]. Consequently, in the absence of natural producers of
quinolones, the presence of acquired resistance among pathogens
is unlikely. Nevertheless, the acquired resistance to quinolones
exists and is due to the qnr genes, which encode a 218-aa protein
belonging to the pentapeptide repeat family, with a sequence
homology to the immunity protein McbG [222]. This quinolone
resistance mechanism is via the binding of Qnr to DNA gyrase in
the early stages of gyrase-DNA complex formation, and, by lower-
ing gyrase binding to DNA, Qnr may reduce the amount of
holoenzyme-DNA targets for quinolone inhibition [223]. The genes
encoding the pentapeptide repeat family proteins are common
among bacteria in many ecosystems, and the phylogenetic analysis
suggests that the qnr genes in pathogens have been probably
acquired from marine bacteria [5]. It has been suggested that one
of the pentapeptide repeat family proteins, MfpA, provides a topo-
logical assistance to DNA when needed, but also helps to maintain
it in a condensed state, hence preventing undesired topological
changes during the replicative senescence periods [105]. Thus,
the probable scenario for the acquired resistance to quinolones is
that the DNA metabolism enzyme of environmental bacteria
appeared to be also protective against this synthetic antibiotic.
The frequency of horizontal gene exchange among bacteria of dif-
ferent ecological compartments is high [8,9]. Once transferred to
other, probably commensal, microbiota and subjected to a strong
selective pressure, the corresponding qnr genes disseminated,
eventually entering the pathogenic microbiota [5].
Despite being a product of an entirely chemical synthesis, struc-
turally similar compounds can be found in natural ecosystems as
well. The species of Pseudomonas and some other bacteria produce
a quorum-signaling molecule, 2-heptyl-3-hydroxy-4-quinolone,
which belongs to the family of 2-alkyl-4-quinolones [70]. Initially,
however, these compounds were defined as antimicrobials for
their corresponding activities [103]. The abundance of natural qui-
nolones appeared to be underestimated: several plant, animal, and
microbial species may produce them [104]. Then, potentially, qui-
nolone resistance may have appeared as a protective mechanism
against these naturally produced substances.
16. Lincosamides
The first antibiotic of this class discovered was lincomycin,
which is produced by Streptomyces lincolnensis var. lincolnensis
strain and was made available for clinical studies in January
1963 by Upjohn [145]. It has a rather narrow range of bacterial
pathogens targeted, has considerable side effects, and is presently
rarely used in the therapy of infectious diseases. Much broader are
the applications of clindamycin, which is obtained from lincomycin
by introducing a chlorine atom with the inversion of chirality [36].
10 R. Aminov / Biochemical Pharmacology xxx (2016) xxx–xxx
Table 1
History of discovery of main
antimicrobial classes.
Arsphenamines 1910
b-Lactams 1929
Sulphonamides 1935
Polypeptides 1939
Aminoglycosides 1943
Tetracyclines 1945
Amphenicols 1947
Lipopeptides 1947
Macrolides 1950
Oxazolidinones 1952
Glycopeptides 1953
Streptogramins 1953
Ansamycins 1957
Quinolones 1962
Lincosamides 1963
It has lesser side effects compared to the original drug and is used
for the treatment of many anaerobic infections [44]. Its use, how-
ever, may be associated with the hospital-acquired Clostridium dif-
ficile-associated diarrhoea [221]. As mentioned before, the
structurally unrelated macrolides, lincosamides and streptogramin
B, share a common mode of action, which is modulated by the
space available between the peptidyl transferase centre and the
drug [219]. Thus, the modification and protection of the target site
by the erm gene-encoded methylases confer resistance to all these
classes of drugs, including lincosamides [237].
17. Concluding remarks
Currently we are facing a global antibiotic crisis because of the
alarmingly growing antimicrobial resistance among many human
pathogens The mortality rate due to antimicrobial resistant infec-
tions is at least 50,000 each year across Europe and the US alone,
with many hundreds of thousands more dying in other areas of
the world [168]. If no immediate actions are taken, the estimated
death toll due to the antimicrobial resistance will reach 10 million
by the year 2050, surpassing the mortality rate, for example, of
cancer. It has to be emphasized here that all major classes of
antimicrobials were discovered during the golden age of antibiotic
discovery, which came to the end more than 50 years ago (Table 1).
Since then, principal activities in the new antimicrobial drug devel-
opment have been focused, largely, on extensive modifications of
existing natural drugs, and also performed by reengineering and
complete chemical synthesis, if cost-effective. The older antimicro-
bials can still be useful and their therapeutic use optimised, which
allows extracting their antimicrobial potential to the full. In partic-
ular, one of the pharmacokinetic and pharmacodynamics (PK/PD)
strategies, front-loading, may allow a more therapeutically effec-
tive use of some ‘‘old” antibiotics such as colistin [183]. More PK/
PD data on the efficacy and toxicity ranges may provide recom-
mendations for the optimal use of this antimicrobial as well
[169]. Combining antibiotics that display synergistic interactions
is also a promising strategy for the extension of the useful life of
some older antibiotics [40].
The strategies for other potential natural antimicrobials discov-
ery routes could be the exploitation of other ecological compart-
ments and taxonomic groups besides the well-known soil
Actinomycetes. These could include the isolation of antibiotic pro-
ducer strains, for example, from the marine environment
[181,111] or retrieving the antimicrobial biosynthetic pathways
from the uncultivated part of environmental microbiota via the
metagenomic approach [146]. The source of antimicrobials could
be also enriched by antimicrobial peptides and compounds from
animals and plants [101] or by mimicking the natural bacterial
Please cite this article in press as: R. Aminov, History of antimicrobial drug discovery – Major classes and health impact, Biochem. Pharmacol. (2016),
http://dx.doi.org/10.1016/j.bcp.2016.10.001
and fungal lipopeptides [147]. Finally, it could be the use of the
complete synthetic routes pioneered during the early years of the
antibiotic era, as in the case of sulphonamides, but with the current
knowledge of bacterial targets and possibilities of in silico modeling
of drug-target interaction. The latter approach becomes dominant
in the search for drugs aimed at the newly identified targets in a
bacterial cell. Other strategies may include drugs engineered to
possess dual target activities, such as a rifamycin-quinolone hybrid
antibiotic, CBR-2092 [188], or the previously mentioned chimeric
streptogramin-tyrocidine antibiotics [157] and the combination
of other antimicrobials with amphenicols [68].
The need for new antibiotics is urgent [164,217]. For a variety of
reasons, however, big pharmaceutical companies have largely
abandoned the antimicrobial research area [31]. Thus the level of
investment into the development of novel antimicrobials is not
sufficient to meet the growing and urgent demands. In this regard,
the change of paradigms under which the regulatory agencies and
pharmaceutical industry operate can help to address the unmet
demands for new antimicrobials [31]. The suggestions proposed
include the development of a new business model for antimicro-
bials, which is considerably different from that for other pharma-
ceuticals, and will separate the return on investment from
antibiotic sales volume [56]. To compensate for potential business
deficiency implemented under this model, it calls for a much
broader involvement of governments in financial support of antibi-
otic R&D, in particular by a broad menu of incentives across the
antibiotic life-cycle, with the highest incentives targeted at the
development of antibiotics directed at the greatest health threats
arising from antibiotic resistance. It is envisaged that contributions
from the governments of different countries should be coordinated
within a globally agreed framework [56]. The first practical steps in
this direction can be already seen in the form of the establishment
of a new global public–private partnership to support antibiotic
innovations called CARB-X [170]. CARB-X will invest more than
US$350 million in the next 5 years to accelerate the advancement
of a diverse range of innovative antimicrobials into clinical trials.
We have to keep in mind, however, that even with newer and
better antimicrobials introduced, there is always a risk that the
microbes may eventually develop resistance against them. More-
over, no exception to this scenario has ever been seen: the devel-
opment of resistance is just a question of time and the
antimicrobial use practices involved. Thus, limiting the emergence
and dissemination of antimicrobial resistance remains one of the
important cornerstones of antimicrobial stewardship to prolong
the useful lifespan of these drugs.
There is a direct correlation between the level of antibiotic use
and corresponding resistance [94], which is perfectly understand-
able from the biology point of view: the broader a selection is,
the higher is the chance for the trait selected, that is antibiotic
resistance, to appear [5]. The human antibiotic consumption and
the use of last-resort antibiotics are on the rise [229]. While we
cannot easily judge what is right and what is wrong in the use of
antibiotics in humans for treatment of infectious diseases, the
other uses may be confronted and addressed to. It seems obvious
that the use of antibiotics has to be limited to the approved and
controlled treatment of bacterial infectious diseases, both in
humans and animals, but presently this is not the case. Several
estimates, for example, suggest that a substantial proportion of
antibiotics produced are used in food animals for non-
therapeutic purposes [132,128]. Extensive literature suggesting
an epidemiologic link between the antibiotic use in food animals
and antibiotic resistance in humans has been also compiled
[132]. Unfortunately, however, the global use of antimicrobials in
food animals is predicted to grow rapidly, by at least 67% from
2010 to 2030 [230]. In the BRICS countries (Brazil, Russia, India,
China, and South Africa) the antimicrobial consumption by live-
 R. Aminov / Biochemical Pharmacology xxx (2016) xxx–xxx
stock will be doubled. The total amount of antibiotics produced for
this purpose will reach 105,596 ± 3605 tons in 2030 from
63,151 ± 1560 tons in 2010 [230]. It is estimated that about a third
of this increase will be due to the switch from extensive farming
systems to large-scale intensive farming operations that routinely
use antimicrobials at sub-therapeutic concentrations [230]. It is
clear that there are certain economic drivers for this development
in livestock production. But should these considerations also
include the costs that are eventually paid by the society for the
development of new antimicrobials, for more expensive treatment
of MDR infections and, finally, for the higher morbidity and mortal-
ity rates imposed by MDR infections? These extremely worrying
trends dictate the need for global and coordinated actions to pre-
vent the overuse of antibiotics and the subsequent rise of antibiotic
resistance. Otherwise, the newly developed antimicrobials may
succumb to the same destiny as those ‘‘old” antimicrobials
described here.
Conflict of interest statement
The author declares that the work was conducted in the absence
of any commercial or financial relationships that could be con-
strued as a potential conflict of interest.
Author contribution statement
The corresponding author contributed 100% of the submission.
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