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
Email: rustam.aminov@abdn.ac.uk


Conflict of interest statement
The author declares that the work was conducted in the absence of any commercial
or financial relationships that could be construed as a potential conflict of interest.

Author contribution statement
The corresponding author contributed 100% of the submission.

Abstract

The introduction of antibiotics into clinical practice revolutionized the

treatment and management of infectious diseases. Before the introduction of

antibiotics, these diseases were the leading cause of morbidity and mortality in
human populations. This review presents a brief history of discovery of the main
antimicrobial classes (arsphenamines, -lactams, sulphonamides, polypeptides,
aminoglycosides,

tetracyclines,

amphenicols,

lipopeptides,

macrolides,

oxazolidinones, glycopeptides, streptogramins, ansamycins, quinolones, and

lincosamides) that have changed the landscape of contemporary medicine. Given
within a historical timeline context, the review discusses how the introduction of
certain antimicrobial classes affected the morbidity and mortality rates due to
bacterial infectious diseases in human populations. Problems of resistance to
antibiotics of different classes are also extensively discussed.

Keywords: Antimicrobial drug discovery; History.

1. Introduction

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 (Armstrong et al.,
1999). Infectious diseases that mostly contributed to this sharp decline were
pneumonia, influenza, and tuberculosis. These declines corresponded to the
introduction into clinical practice of sulphonamides in 1935, penicillin in 1941, and
streptomycin in 1943, with a number of other combination drugs, such as paraaminosalicylic acid in 1944 and isoniazid in 1952, introduced for tuberculosis
treatment in addition to streptomycin (Baldry, 1976). This correlation clearly
indicates the importance of antimicrobials in the control of infectious diseases. A
recent statistics 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 Statistics Reports, among the 15 leading
causes of death in the USA, infectious diseases, such as influenza and pneumonia, are
superseded by heart disease, cancer, chronic lower respiratory diseases, accidents,

stroke, Alzheimers disease, and diabetes (Xu et al., 2016). 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.

2. Arsphenamines and the foundation of modern antimicrobial chemotherapy

Paul Ehrlichs 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 reasoned 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 synthesized by Antoine

Bchamp in 1859 (Burke, 1925; Steverding, 2010), initially for the treatment of
African sleeping sickness. This drug attracted the attention of Paul Ehrlich and Alfred
Bertheim, an organic chemist working with him. They correctly identified the
chemical structure of this compound as aminophenyl arsenic acid, thus opening the
possibility of synthetizing various derivatives in the search for a more efficient 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 (Ehrlich and Hata,
1910). This process of systematic synthesis and activity check is considered to be the
beginning of the modern chemotherapeutic era (Stefan and Kaufmann, 2008). Almost
all further developments in modern pharmaceutical research followed this route,
with systematic chemical modifications of a lead compound to improve its biological
activity and lessen the side effects.

Despite the problems associated with its stability and storage, as well 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 prescribed drug
until its replacement by penicillin in the 1940s (Mahoney et al., 1943). 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 (Lloyd et al., 2005).
Other derivatives of the lead compound, arsanilic acid, however, have been in a much
more prolonged use as feed additives in poultry and swine. The U.S. Food and Drug
Administration (FDA) announced the complete withdrawal of arsenic-based drugs
for use in food-producing animals only by the end of 2015 (FDA, 2015a).

Presently, syphilis infections are successfully managed by penicillin 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 delivery. Patients with severe allergy to penicillin can be treated with
tetracycline or doxycycline. The availability of very efficient therapies resulted in a
substantial drop of mortality due to syphilis, from 202,000 in 1990 to 113,000 in
2010 (Lozano, 2012). Still, the number of new infections remains relatively high,
with 315,000 cases reported in 2013 (Collaborators, 2015).

3. -lactams

Discovered serendipitously in 1928 by Alexander Fleming (Fleming, 1929),

penicillin did not immediately take off as a clinically useful antibiotic. 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 infections, 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 previously untreatable infectious
diseases, with a wider range of targets 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 Penicillium fungi from time to time (e.g., Vincenzo Tiberio,
see Bucci and Galli, 2011), it was Alexander Flemings 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 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 (Chain et al., 2005). The following refinements
and optimizations of the original procedure, isolation of more efficient penicillin
producer strains, and optimization of the strain fermentation procedure eventually
led to the mass production and distribution of penicillin in 1945 (Parascandola,
1980).

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 antibiotic discovery programmes.

Identification of 6-aminopenicillanic acid as the core of penicillin by scientists

of Beecham Research Laboratories in the UK (Batchelor et al., 1959) allowed the

synthesis and production of numerous semisynthetic 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 ticarcillin), and the ureidopenicillins
(mezlocillin, azlocillin, and piperacillin) (Wright, 1999). Further developments to
overcome resistance and extend the range of targeted organisms led to the
combination of a -lactamase inhibitor (clavulanic acid, sulbactam, or tazobactam)
and an aminopenicillin, ticarcillin, or piperacillin (Wright, 1999). Although unified
under the umbrella of the -lactam structure, this group of antibiotics is sometimes
separated into the penicillin, cephalosporin, and carbapenem classes. These are the
most frequently prescribed broad-spectrum antibiotics in outpatient care (Lee et al.,
2014; Shapiro et al., 2014), and, as such, may have contributed to a significant
problem of resistance towards -lactams among pathogenic bacteria (Boucher et al.,
2009).

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 extensive use of penicillin, some observations
suggested that bacteria could destroy it by enzymatic degradation (Abraham and
Chain, 1940). The outlook, however, 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 infections, 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 (Rollo et al., 1953). Surprisingly, this is still true for
syphilis infections (Cha et al., 2004), 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 (Kumarasamy et al., 2010).

The rise of ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus,

Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and

Enterobacter spp.) (Rice, 2009; Boucher et al., 2009) represents an especially
worrying trend. Although the majority of these infections 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 microbial
world has accumulated an enormous diversity of metabolic and protective
mechanisms than can be mobilized in response to a strong selection, including the
pressure of antibiotics (Aminov, 2009; Aminov, 2010). Despite being obstructed by
the growing resistance problem, the -lactam antimicrobials remain the most widely
prescribed anti-infective agents due to their safety, efficacy, and availability (Lee et
al., 2014; Shapiro et al., 2014). Strategies for the further development of this class of
antimicrobials may include the novel broad-spectrum -lactamase inhibitors that
work against many problematic -lactamases such as cephalosporinases and
carbapenemases (Bush and Bradford, 2016). This could also be the combination of
two non--lactam families of -lactamase inhibitors, diazabicyclooctanes and boronic
acids, with novel or existing -lactam antibiotics (King et al., 2016). Besides, the
conjugation of -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 (King et al., 2016).

Another biological activity of -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 glutamate transporter subtype 1 (Rothstein et al.,
2005). Glutamate is a principal excitatory neurotransmitter in the brain involved in
memory and learning processes (Shigeri et al., 2004). 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 (Aminov, 2013a). Thus, the use of -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 antimicrobials 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 parasites, 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 (KI730, 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 (Domagk, 1935). 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
(Trfoul et al., 1935). 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 companies subsequently started mass production of
sulphonamide derivatives. Some of the preparations, however, included diethylene
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/FederalFoodDrugandCos
meticActFDCAct/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% decline in maternal mortality, a 1732% decline in pneumonia mortality, and a 52-65% decline in scarlet fever mortality
(Seema et al., 2010). Overall, sulpha drugs reduced mortality by 2 to 3 per cent and
increased life expectancy by 0.4 to 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
sulphonamides include their use as anti-diabetics, diuretics, anticonvulsants, 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 case

of drug resistance, i.e. sulpha drug resistance, which is almost universally linked with
class 1 integrons. Mobile genetic elements (MGEs) have been instrumental in the
rapid dissemination of antimicrobial resistance genes (Aminov, 2011). Moreover,
once the sulpha drug resistance is established on an MGE, it may be difficult to
eliminate, because the resulting construct confers a fitness advantage to the host
even in the absence of antibiotic selection (Enne et al., 2004). Despite this, many
continuously modified derivatives of this oldest class of synthetic antibiotics are still
a viable option for therapy, while the action of and resistance to sulphanilamides 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 species appeared to be producing a variety of linear and cyclic
peptides using nonribosomal protein synthetases (Kopp and Marahiel, 2007).
Tyrothricin isolated by Ren Dubos, an American microbiologist of French origin, 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
contain 10 modules (Roskoski et al., 1970). Another cyclic polypeptide, from another
strain of B. brevis, gramicidin S (S stands for Soviet), was reported in 1944 (Gause
and Brazhnikova, 1944). Other gramicidins, A, B, and C, as well as the mix of these
three called gramicidin D, are the linear pentadecapeptides (Burkhart et al., 1999).
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 gramicidins 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 synthesized ribosomally by
various species of mushrooms, and can be extremely toxic (Hallen et al., 2007).

The use of gramicidins and other polypeptides, however, is limited 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 (Urry, 1977; Prenner et al., 1997). In animals and humans,
this activity, at concentrations lower than needed to achieve the bacterial 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
exceptional cases, however, they can be used systemically as last resort antibiotics
when other options are exhausted, for instance in the case of resistance or
contraindication such as allergy (Bacitracin, 2010).

6. Aminoglycosides

In 1943, Selman Abraham Waksman headed a research team at Rutgers

University in the search for new antibiotics (Waksman, 1964). 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 (Wainwright, 1991; Lawrence, 2002; Kingston, 2004;
Wainwright, 2005). Clinical trials in the following year demonstrated 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
four-fold in a decade (from 1945 to 1955), from 39.9 deaths per 100,000 population
to 9.1 (Groves and Hetzel, 1968). 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" (Waksman, 1964).

10

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 (Plikaytis et al., 1994). According to WHO Fact Sheet
N104, 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 rifampicin poses a major problem restricting the available therapeutic
choices. The situation is further aggravated by the emergence of extensively drugresistant tuberculosis (XDR-TB), which, in addition, 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-tbfaq/en/index.html).

As early as in 2007, two tuberculosis cases that resisted all available drugs

and long-term (5 to 8 years) treatments and eventually resulted in the death of both
patients were reported in Italy (Migliori et al., 2007). In 2009, the emergence of new
forms of resistant M. tuberculosis strains, totally drug-resistant (TDR), was also
documented in Iran (Velayati et al., 2009). 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 (Udwadia et al., 2012; Klopper et al.,
2013).

Although presently relatively rare, these cases demand immediate actions

geared towards the rapid identification and containment of these dangerous strains
to prevent further outbreaks of untreatable TB (Velayati et al., 2013). 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 (FDA, 2012).
Unlike other quinolones, the molecular target of this antibiotic is mycobacterial ATP
synthase, not DNA gyrase. Targeting energy metabolism may thus represent a new,

11

promising approach for antibacterial drug discovery (Andries et al., 2005; Koul et al.,
2007). There are a number of compounds at various stages of clinical and preclinical
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 (Krause et al., 2016). There is, however, a renewed interest in
aminoglycosides due to the ever-increasing problem of antibiotic resistance. In
particular, gentamicin is still widely used in hospital settings for treatment of serious
infections (Kushner et al., 2016). Amikacin is commonly used in intensive care units
for the treatment of patients with life-threatening Gram-negative infections (Marsot
et al., 2016). Aminoglycosides display synergistic activities in combination with other
antibiotic classes, while the safety and efficacy issues can be potentially solved via
PK/PD-based optimized therapy regimens.

7. Tetracyclines

The first antibiotic of this class, chlortetracycline, was discovered in 1945 by

Benjamin Minge Duggar under the supervision of Yellapragada Subbarow at Lederle

Laboratory Division of American Cyanamid Company (Duggar, 1948). The antibioticproducing soil bacterium 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 prescriptions were issued within a timeframe that is almost
unimaginable 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 (Wright and Schreiber, 1949).

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. aureofaciens, left after the

12

fermentation and extraction of Aureomycin, on chickens. This discovery occurred

during their search for sources of vitamin B-12, and the debris of S. auerofaciens
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 additives 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 global 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 prohibited 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 authorized feed additives
(EPC, 2005; Castanon, 2007).

In a parallel drug discovery programme, which was a collaborative effort

between Pfizer and Harvard University, the research team discovered and resolved
the chemical structure of another tetracycline antibiotic, oxytetracycline (trade
named Terramycin) (Hochstein et al., 1953). 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-carboxamide skeleton,
substituted with many hydroxy and other groups (IUPAC, 1997). 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 (Nelson and Levy, 2011).

Another interesting aspect of tetracyclines is that there are indications 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 (Bassett et al., 1980). 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

13

cancellous, endocortical, intracortical, and periosteal bone (Lindsay et al., 2013). The
presence of tetracycline incorporated in bones of ancient Sudanese Nubians is only
explicable 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 (5501450 CE) (Hummert et al., 1982). 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 (Nelson
et al., 2010).

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 (Cook et al., 1989). The samples
demonstrated discrete fluorochrome labelling consistent with the presence of
tetracycline, thus suggesting its intake with the diet in the late Roman period (Cook
et al., 1989). The hypothesized 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 infection were detected in the
samples from the Dakhleh Oasis (Armelagos, 1969; Cook et al., 1989). There was no
correlation, however, between the exposure to low concentrations of tetracycline
and disease incidence in the medieval population of Sudanese Nubia (Hummert et al.,
1982).

As mentioned before, the extensive use of tetracyclines in clinical 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 (FDA, 2015b). 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 (FDA, 2015b).
Besides, the non-clinical use of tetracyclines was extended to aquaculture and
horticulture (Chopra and Roberts, 2001). The clinical use of the first-generation
tetracyclines, however, progressively decreased due to the widespread resistance
towards this antibiotic class. The most common mechanisms of resistance are the
efflux of tetracycline from the cell and ribosomal protection, where tetracycline is

14

prevented from binding to the ribosome because of the synthesis of alternative

elongation factors (Chopra and Roberts, 2001). The less conspicuous mechanisms of
tetracycline resistance included the enzymatic degradation of tetracycline (Speer et
al., 1991) and, presumably, a metabolic mechanism protecting against the entry of
the antibiotic into the cell (Kazimierczak et al., 2009). The wide dissemination of
antibiotic resistance genes is facilitated by their location on MGEs, allowing an
almost indiscriminate exchange among a variety of taxonomic entities (Aminov,
2011).

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 (Redin, 1966)) and doxycycline (available from
1967 (Corey, 2013)). They are used to treat many different infectious diseases, such
as urinary and intestinal tract infections, respiratory infections, skin infections, acne,
gonorrhoea, tick fever, chlamydia, eye infections, periodontitis, and others. Besides
the antibacterial effects, they also display other potent activities directed towards the
eukaryotic cell targets (Aminov, 2013a). In particular, minocycline displays strong
anti-inflammatory, neuroprotective, anti-proteolytic, and anti-apoptotic properties,
as well as inhibits angiogenesis and metastatic growth (Garrido-Mesa et al., 2013). In
addition, it displays antioxidant activity, inhibits several enzyme activities, and
modulates immune cell activation and proliferation (Aminov, 2013a).

In June 2005, tigecycline, the first representative of the third-generation

tetracyclines (also called glycylcyclines), was approved by the FDA (Rose and Rybak,
2006). It is administered intravenously to treat complicated skin and intraabdominal 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 performed (Pournaras et al., 2016). 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 significant problem in controlling
resistance to this antibiotic (Aminov, 2013b).

15

8. Amphenicols

Chronologically, the next antibiotic in the pipeline of the antibiotic 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 advantageous, and
chloramphenicol became the first antibiotic produced synthetically on an industrial
scale (Dinos et al., 2016). 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 -lactams or in
patients with other serious infections when alternative medications are
contraindicated or inefficient (Eliakim-Raz et al., 2015). 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 (Brunton et al., 2005).

To circumvent the toxicity and side effect problems, a number of other

amphenicol derivatives have been synthesized (Dinos et al., 2016), and some of them,
such as thiamphenicol, azidamfenicol, and florfenicol, have even entered into clinical
and veterinary practice. The relatively simple molecule of chloramphenicol opened
the possibility of constructing hybrid antibiotics, where the segments of two drugs
are covalently connected into one molecule (Dinos et al., 2016). Besides
antimicrobial activities, this class of drugs may find potential applications in cancer
therapy (Dinos et al., 2016).

The most frequently encountered mechanism of resistance towards

chloramphenicol is its enzymatic inactivation by acetylation, via different types of

chloramphenicol acetyltransferases (Schwarz et al., 2004). Less frequent are the
efflux of chloramphenicol, its inactivation by phosphotransferases, target mutations,
and permeability barriers.

16

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 (Storm et al., 1977). 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 (Evans et al., 1999). With the emergence and dissemination of Gramnegative bacterial pathogens that are resistant to the mainstream treatment with the
aminoglycosides, -lactams, and quinolones, there is a renewed interest in the use of
colistin. It can be used as a last resort antibiotic against serious and difficult-to-treat
infections such as those caused by multidrug-resistant P. aeruginosa, K. pneumoniae,
and A. baumannii (Falagas et al., 2008). Multidrug-resistant isolates of the
Enterobacteriaceae expressing the novel NDM-1 metallo--lactamase still remain
susceptible to colistin (Kumarasamy et al., 2010).

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 negatively charged LPS molecules (Falagas and Kasiakou, 2005). This
results in a local disturbance 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 (Liu et al., 2016). 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 (Napier et al., 2013). Colistin selection for
pathogen resistance against the first line of hosts 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 (Tally and DeBruin, 2000). It was discovered by

researchers at Eli Lilly and Company in early 1980s but did not enter the clinical

17

practice until 2003 (Steenbergen et al., 2005). 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 eventual breach in the cell
membrane integrity and cell death (Pogliano et al., 2012). The antibiotic is well
tolerated, with the frequency and distribution of adverse effects similar to
comparator drugs (Rybak, 2006). Resistance to daptomycin remains rare. In S.
aureus, it is the result of incremental accumulation of point mutations in genes
encoding a lysylphosphatidylglycerol synthetase, a histidine kinase, and RpoB and
RpoC subunits of RNA polymerase (Friedman et al., 2006). There is a good potential
for the development of various daptomycin derivatives using a biosynthetic
engineering approach (Baltz, 2009).

A group of lipopeptides called echinocandins display potent antifungal

activities (Denning, 2002). They noncompetitively inhibit -(1,3)-D-glucan synthase,

an essential enzyme complex for the synthesis of glucan in the fungal cell wall
(Morris and Villmann, 2006). They were discovered in 1970s during extensive
screening programmes for antifungals with a broad-spectrum activity against the
species of Candida. 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 caspofungin, micafungin, and anidulafungin
(Morris and Villmann, 2006). In a recent report by the Centers for Disease Control
and Prevention regarding the microorganisms with a serious threat level, the only
fungal pathogen among the 12 most serious threats is a fluconazole-resistant
Candida (CDC, 2013). Thus the echinocandins serve as a valuable first-line treatment
option against these serious fungal infections. Resistance to the echinocandins is
rare, essentially limited to the case studies with the resistance emerging during the
treatment (Eschenauer et al., 2007).

10. Macrolides

The first antibiotic of the macrolide class, pikromycin, was isolated from

Streptomyces venezuelae by Brockmann and Henkel in 1950 (Brockmann and Henkel,

1950; Brockmann and Henkel, 1951). It has not advanced to clinical use but still

18

remains an important precursor for the synthesis of other macrolides and

derivatives (Kittendorf and Sherman, 2009). The first commercially successful
macrolide, erythromycin (also known as Ilosone or Ilotycin to reflect the soil sample
collection place in the Iloilo region in the Philippines), was discovered by the team of
scientists led by J. M. McGuire at Eli Lilly (McGuire et al., 1952). 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, Saccharopolyspora
erythraea (formerly Streptomyces erythraeus), was published in 2007 (Oliynyk et al.,
2007).

Structurally, the natural macrolides consist of a large macrocyclic 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 (Khosla et al.,
1999; Jenke-Kodama et al., 2005). Besides the macrolide biosynthesis, polyketide
synthases are also involved in the biosynthesis of many other biologically active
secondary metabolites. These include a broad range of compounds covering other
antibiotic

classes

such

as

tetracyclines,

as

well

as

immunosuppressants/immunomodulators, and anticholesterol and anticancer drugs

(Koehn and Carter, 2005). In terms of infection control, the macrolides are possibly
the second most prescribed antibiotic class after the -lactams, targeting a similarly
broad range of bacterial pathogens, although with a lesser efficiency against Gramnegative bacteria. The obvious advantage of the macrolides over the -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 antimycotics, consists of antibiotics
active against fungal infections, and these include amphotericin B, nystatin, and
others (Hamilton-Miller, 1973).

Various modifications of natural macrolides have been performed to improve

the pharmacokinetic properties of antibiotics in this class, such as the use of the
azalide scaffold (Ituk et al., 2011; Sugimoto et al., 2012). This approach was initially
implemented in the synthesis of 9-dihydro-9-deoxo-9a-methyl-9a-aza-9a-

19

homoerythromycin A (azithromycin) by the Croatian pharmaceutical company Pliva

in 1980 (Greenwood, 2008). The antibiotic displays outstanding pharmacokinetic
properties, including the lack of inhibition of cytochrome P450 3A4 (Amsden, 2001;
Mutak, 2007). It was the most prescribed antibiotic for outpatients in the US in 2010
(Hicks et al., 2013). With other macrolides, this group of antibiotics is among the
most frequently prescribed anti-infective drugs in outpatient care (Lee et al., 2014;
Shapiro et al., 2014).

Further efforts to improve the antibacterial activities of macrolides have been

focused on increasing the affinity to the target and the capability to bind to a larger
number of sites on the ribosome target. These works have led to the development of
ketolides and fluoroketolides. The first and the only approved ketolide drug,
telithromycin, 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
neutral 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 (Scheinfeld, 2004). Other modifications
included the addition of a carbamate ring in the lactone ring, attachment of an alkylaryl moiety to the carbamate ring, and methylation of carbon at position 6. The
affinity 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, whilst a strong binding of older macrolides is limited only to one domain,
with a weak binding to the second domain. The significant advantage of this design is
that telithromycin is also active against bacteria 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 (Weisblum 1995). 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 (Llano-Sotelo et al., 2010). It also lacks the

20

pyridine-imidazole group present on the side chain of telithromycin, which acts as an

antagonist of various nicotinic acetylcholine receptors and thus causes off-target
undesirable side effects (Bertrand et al., 2010).

Besides the antimicrobial use, the macrolides have demonstrated 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 (Kudoh et al., 1987). 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 (Nagai et al., 1991). Other pulmonary diseases, for which the
non-antimicrobial therapeutic effect of macrolides has been demonstrated, include
cystic fibrosis (Lutz et al., 2012), asthma (Good et l., 2012), and chronic obstructive
pulmonary disease (Seemungal et al., 2008). Furthermore, the positive nonantimicrobial therapeutic effect of macrolides has been demonstrated in
cardiovascular diseases, autoimmunity, prophylaxis of transplant rejection, and a
number of other conditions (Aminov, 2013a). Allegedly, these therapeutic effects of
macrolides are due to their anti-inflammatory properties (Aminov, 2013a).

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 orientomycin (Bartmann
et al., 2013). 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 (Stammer et al., 1955). 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 (Prosser and Carvalho, 2013). The drug is a second-line antibiotic used
in the treatment of tuberculosis, particularly of MDR M. tuberculosis infections (WHO,
2006). The recently uncovered resistance mechanism of M. tuberculosis towards D

21

cycloserine involves the loss-of-function mutations in ald (Rv2780), which encodes

the L-alanine dehydrogenase (Desjardins et al., 2016).

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 (Shinabarger,
1999). 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 (Slee et
al., 1987; Brickner, 1996). While active in vitro, they were, however, too toxic,
affecting in particular the liver, in order to be useful in clinical applications. Finally,
the oxazolidinone research program at Pharmacia & Upjohn (now part of Pfizer)
resulted in a relatively safe antimicrobial, linezolid (Moellering, 2003; French, 2003),
which was approved by the FDA in 2000 and, shortly thereafter, by the
corresponding 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 (Pfizer, 2010). It is not clinically effective against Gramnegative pathogens as a result of endogenous efflux activity in these organisms
(Livermore, 2003). Although relatively safe during short-term treatments, a more
prolonged use may result in peripheral or optical neuropathy, most likely due to the
mitochondrial toxicity of the drug (Soriano et al., 2005; Barnhill et al., 2012).
Resistance 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% intermediate) (Jones et al., 2009). Other drugs in this group include
tedizolid, which was approved by the FDA in 2014 (FDA, 2014), and a number of
other oxazolidinones is currently under the various stages of development.

12. Glycopeptides

This class consists of antibiotics composed of glycosylated cyclic or polycyclic

peptides synthesised nonribosomally. The first representative of the class,

vancomycin, was discovered in 1953 by Edmund Kornfeld and the team at Eli Lilly in
the producer bacterium Amycolatopsis orientalis (formerly Streptomyces orientalis

22

and Nocardia orientalis), which was isolated from the soil sample brought from
Borneo (Shnayerson and Plotkin, 2003; Levine, 2006). 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 complicated infections of the lower respiratory tract, skin, and
bones caused by Gram-positive bacteria (Boneca and Chiosis, 2003). The emergence
and dissemination of VRE (Arias and Murray, 2012), vancomycin-intermediate S.
aureus (VISA) (Hiramatsu et al., 1997), and vancomycin-resistant S. aureus (VRSA)
(Chang et al., 2003; Gardete and Tomasz, 2014) may represent a significant problem
for healthcare facilities such as hospitals. There are suggestions that the agricultural
growth-promoting use of another glycopeptide antibiotic, avoparcin, may have
contributed to the wide dissemination of vancomycin resistance (Bager et al., 1997;
Collignon, 1999; Acar et al., 2000).

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 dipeptide D-Ala-D-Ala on the end of the precursor peptide chains,
thus preventing transpeptidation and transglycosylation, which halts the crosslinking of the cell wall, and leads to cell lysis and death (James et al., 2013). 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 (Arthur et al., 1996). Another
modification of the terminal dipeptide to D-Ala-D-Ser may also offer protection
against the drug but at a much lower level (Pootoolal et al., 2002). An interesting and
valuable approach has been proposed to overcome this type of resistance by
reengineering vancomycin to confer a dual binding capability to D-Ala-D-Ala and DAla-D-Lac, with a resulting significant activity against VanA VRE (Crowley and Boger,
2006). 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 (Xie et al., 2011; Xie et al.,
2012; Okano et al., 2014; Okano et al., 2015).

23

The second natural antibiotic of this class, teicoplanin (formerly named

teichomycin) was isolated from Actinoplanes teichomyceticus and described in 1978

(Parenti et al., 1978; Bardone et al., 1978). Teicoplanin actually represents a mixture
of several compounds consisting of five major components (A2-1 through A2-5), one
hydrolysis component (A3-1), and four minor components (RS-1 through RS-4)
(Bernareggi et al., 1992). The components 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 (Murphy and Pinney, 1995). Thus
teicoplanin may have pharmacoeconomic advantages over vancomycin in at least of
treatment of similar Gram-positive bacterial infections (Spencer and Bryson, 1995;
Wood, 1996). Teicoplanin remains active against vancomycin resistance caused by
VanB and VanC, but is not active against VanA resistant strains (Parenti et al., 2000).
According to a large European survey, however, the resistance levels among Grampositive bacterial pathogens during 1995 were similar towards the two antibiotics
(Grneberg and Hryniewicz, 1998).

The currently approved second-generation glycopeptides include telavancin

(approved by the FDA in 2009), and oritavancin and dalbavancin (both approved in
2014) (Binda et al., 2014). In addition to the classical 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 (Zhanel et al., 2010). The multiplicity of
targets makes them extremely potent, surpassing the potency of vancomycin by 4- to
8-fold (Klinker and Borgert, 2015). Another advantage of some second-generation
glycopeptides is excellent pharmacokinetics allowing less frequent administrations
such as once-daily for telavancin, once-weekly for dalbavancin, and one dose per
treatment for oritavancin (Van Bambeke, 2006; Zhanel et al., 2010). These
antimicrobials are also called the lipoglycopeptides to reflect the synthetic
modifications made to the parent glycopeptides by the addition of lipophilic tails
(Zhanel et al., 2010; Roberts et al., 2015).

13. Streptogramins

24

Streptogramins have been isolated from many different species of

Streptomyces in the course of numerous antibiotic discovery programmes in many

companies, so it is hard to tell which streptogramin was discovered first (Cocito,
1979). According to available literature, the first description of streptogramin was
published by Charney and others (Charney et al., 1953). Among streptogramins,
probably the most known is virginiamycin, which was (and still is) used extensively
in food animals for growth-promoting purposes (Barnhart et al., 1960; Yates and
Schaible, 1962). 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) (Maxwell et al., 1981). The former is also used in fuel
ethanol production to prevent and treat bacterial contamination during the
fermentation process (Bischoff et al., 2016). Only considerably later, the
streptogramins, such as pristinamycin and quinupristin/dalfopristin, started to be
marketed for human consumption as well (Hamilton-Miller, 1991; Allington and
Rivey, 2001). The targeted pathogens are mainly the strains of VRE and MRSA
(Delgado et al., 2000; Eliopoulos, 2003).

Streptogramin antibiotics are unique in the sense that the producer 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 (Cocito, 1979). 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 (Di Giambattista et al.,
1989). X-ray structural analyses suggests that streptogramin B, which is a cyclic
depsipeptide compound, acts analogously to the macrolides by binding to the
ribosomal exit tunnel and blocking it (Harms et al., 2004). 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 streptogramins, therefore, may be responsible for their
bactericidal activity and the post-antibiotic inhibition of protein synthesis (Harms et
al, 2004).

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 binding to the same site on the 50S ribosomal

25

subunit. Structural studies suggest that macrolidelincosamidestreptogramin 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 (Tenson et
al., 2003). Thus, it is not surprising that there is overlapping resistance to these three
classes of antibiotics. In particular, these are the erm genes that encode methylases,
which dimethylate the adenine residue A2058 in the 23S rRNA component of the 50S
large subunit of the bacterial ribosome (Weisblum 1995). 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 resistance, towards macrolides, lincosamides, and depsipeptides (Leclercq,
2002). Chimeric streptogramin-tyrocidine antibiotics could be potentially helpful in
overcoming streptogramin resistance (Mukhtar et al., 2005).

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 sample
collected in southern France (Margalith and Beretta, 1960). 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 (Thieman et al. 1969), to Amycolatopsis
mediterranei (Lechevalier et al., 1986) and, finally, to Amycolatopsis rifamycinica
(Bala et al., 2004).

The rifamycins appeared to be rather unstable to purify from the culture

broth, except for Rifamycin B, which, unfortunately, was practically inactive (Sensi,
1983). However, it is spontaneously oxidized and hydrolysed in aqueous solutions to
produce the highly active Rifamycin S. Further chemical modifications yielded
Rifamycin 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 limited to intravenous use. Among
further modifications that included several hydrazones of 3-formylrifamycin SV, the
hydrazone with N-amino-N'-methylpiperazine (rifampin or rifampicin) appeared to

26

be suitable for peroral use and, ensuing successful clinical trials, was introduced into
therapeutic use in 1968 (Sensi, 1983).

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 (Martinez-Sandoval et al., 2010). It is also currently investigated
for the treatment of other non-infectious pathologies of the gastrointestinal tract
such as IBS and IBD (Ponziani et al., 2016; Sartor, 2016). Rifalazil is used for the
treatment of persistent chlamydia infections (Rothstein et al., 2007). 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 (Sepkowitz et al., 1995). Other drugs
among ansamycins include antimicrobials, such as naphthomycins (Balerna et al.,
1969) and streptovaricins (Rinehart et al., 1975), as well as an antitumor antibiotic
geldanamycin (Bedin, 2004).

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 (Wehrli and Staehelin, 1971). 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 -subunit
to the drug (Ramaswamy et al., 1998; Floss and Yu, 2005). Other mechanisms of
resistance include duplication of the target, action of RNAP-binding proteins, various
enzymatic modifications of rifamycins, and alteration of cell permeability (Tupin et
al., 2010). Similar to quinolone resistance (see the next section), some of the
rifamycin resistance mechanisms may have the environmental origin (Tupin et al.,
2010; Spanogiannopoulos et al., 2014).

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 (Wentland,

1993). 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

27

quinolones. The division into the generations is fairly arbitrary, except for the first
generation, which is represented by the nonfluorinated drugs, while all later
generations are exclusively fluorinated compounds (usually fluorinated at the C-6 or
C-7 position) and, thus, are commonly called fluoroquinolones. The most known
antimicrobial activity of quinolones is due to the formation of a DNA gyrasequinolone-DNA complex, which blocks the bacterial chromosome replication leading
to cell death (Hiasa and Shea, 2000). Besides bacterial DNA gyrase, quinolones may
also have other targets in the bacterial cell. Bedaquiline, for example, targets energy
metabolism by inactivating ATP synthase (Andries et al., 2005; Koul et al., 2007). In
addition to the antibacterial activities, the 4-quinolone scaffolds exhibit many other
pharmacological properties such as antiviral, antitumor, antiischemic, and anixolytic
activities (Ahmed and Daneshtalab, 2012; Batalha et al., 2016).

Since the synthesis and testing of fluoroquinolones was aimed at targeting a

broad range of bacteria, the approved drugs are suitable 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 -lactams and
macrolides, in the period from 2000 to 2010 (Lee et al., 2014). Within a narrower
and more recent timeframe (2007 to 2009), however, ambulatory prescriptions of
quinolones were the highest (25% of antibiotics), followed by macrolides (20%), and
aminopenicillins (12%) (Shapiro et al., 2014). Thus in recent years the quinolones
became a preferred choice for physicians to treat respiratory and skin/mucosal
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 treatment options (FDA, 2016).

The mechanism of antimicrobial action of fluoroquinolones is mediated via

the formation of DNA gyrase-quinolone-DNA complex blocking the replication

process and thus leading to cell death (Hiasa and Shea, 2000). The mechanisms of
resistance to this class of antimicrobials are of great interest because these are
completely synthetic compounds. It is generally thought that one of the main
contributors of antibiotic resistance genes for dissemination to other bacteria,

28

including pathogens, are the producers of antibiotics, which thus protect themselves
from the lethal action of antibiotics they produce (Wright, 2012). 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 (Tran and Jacoby, 2002). This quinolone resistance mechanism is via the
binding of Qnr to DNA gyrase in the early stages of gyrase-DNA complex formation,
and, by lowering gyrase binding to DNA, Qnr may reduce the amount of holoenzymeDNA targets for quinolone inhibition (Tran et al., 2005). 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 (Aminov and Mackie, 2007). It
has been suggested that one of the pentapeptide repeat family proteins, MfpA,
provides a topological 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 (Hegde et al., 2005). 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 different
ecological compartments is high (Aminov, 2011; Aminov, 2012). Once transferred to
other, probably commensal, microbiota and subjected to a strong selective pressure,
the corresponding qnr genes disseminated, eventually entering the pathogenic
microbiota (Aminov and Mackie, 2007).

Despite being a product of an entirely chemical synthesis, structurally 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-hydroxy4-quinolone, which belongs to the family of 2-alkyl-4-quinolones (Dubern and Diggle,
2008). Initially, however, these compounds were defined as antimicrobials for their
corresponding activities (Hays et al., 1945). The abundance of natural quinolones
appeared to be underestimated: several plant, animal, and microbial species may
produce them (Heeb et al., 2011). Then, potentially, quinolone resistance may have
appeared as a protective mechanism against these naturally produced substances.

29

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 (MacLeod et al., 1964). 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 (Birkenmeyer and Kagan, 1970). It has
lesser side effects compared to the original drug and is used for the treatment of
many anaerobic infections (Brook, 2016). Its use, however, may be associated with
the hospital-acquired Clostridium difficile-associated diarrhoea (Thomas et a., 2003).
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 (Tenson et al., 2003).
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
(Weisblum 1995).

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 infections 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 (ONeill, 2014). 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 development 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
antimicrobials can still be useful and their therapeutic use optimised, which allows

30

extracting their antimicrobial potential to the full. In particular, one of the

pharmacokinetic and pharmacodynamics (PK/PD) strategies, front-loading, may
allow a more therapeutically effective use of some old antibiotics such as colistin
(Rao et al., 2013). More PK/PD data on the efficacy and toxicity ranges may provide
recommendations for the optimal use of this antimicrobial as well (Ortwine et al.,
2015). Combining antibiotics that display synergistic interactions is also a promising
strategy for the extension of the useful life of some older antibiotics (Bollenbach,
2015).

The strategies for other potential natural antimicrobials discovery routes

could be the exploitation of other ecological compartments and taxonomic groups

besides the well-known soil Actinomycetes. These could include the isolation of
antibiotic producer strains, for example, from the marine environment (Rahman et
al., 2010; Hughes and Fenical, 2010) or retrieving the antimicrobial biosynthetic
pathways from the uncultivated part of environmental microbiota via the
metagenomic approach (MacNeil et al., 2001). The source of antimicrobials could be
also enriched by antimicrobial peptides and compounds from animals and plants
(Hancock and Sahl, 2006) or by mimicking the natural bacterial and fungal
lipopeptides (Makovitzki et al., 2006). 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 (Robertson et
al., 2008), or the previously mentioned chimeric streptogramin-tyrocidine antibiotics
(Mukhtar et al., 2005) and the combination of other antimicrobials with amphenicols
(Dinos et al., 2016).

The need for new antibiotics is urgent (Norrby et al., 2005; Talbot et al.,

2006). For a variety of reasons, however, big pharmaceutical companies have largely
abandoned the antimicrobial research area (Bax and Green, 2015). 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 (Bax and Green, 2015). The suggestions

31

proposed include the development of a new business model for antimicrobials, which
is considerably different from that for other pharmaceuticals, and will separate the
return on investment from antibiotic sales volume (Chatham House Report, 2015).
To compensate for potential business deficiency implemented under this model, it
calls for a much broader involvement of governments in financial support of
antibiotic R&D, in particular by a broad menu of incentives across the antibiotic lifecycle, 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 (Chatham House Report, 2015). The first
practical steps in this direction can be already seen in the form of the establishment
of a new global publicprivate partnership to support antibiotic innovations called
CARB-X (Outterson et al., 2016). 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. Moreover, no exception to this scenario has ever
been seen: the development 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 (Goossens et al., 2005), which is perfectly understandable

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 (Aminov and Mackie, 2007).
The human antibiotic consumption and the use of last-resort antibiotics are on the
rise (Van Boeckel et al., 2014). 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 (Landers et al.,

32

2012; Krishnasamy and Silbergeld, 2015). Extensive literature suggesting an

epidemiologic link between the antibiotic use in food animals and antibiotic
resistance in humans has been also compiled (Landers et al., 2012). Unfortunately,
however, the global use of antimicrobials in food animals is predicted to grow
rapidly, by at least 67% from 2010 to 2030 (Van Boeckel et al., 2015). In the BRICS
countries (Brazil, Russia, India, China, and South Africa) the antimicrobial
consumption by livestock will be doubled. The total amount of antibiotics produced
for this purpose will reach 105,596 3,605 tons in 2030 from 63,151 1,560 tons in
2010 (Van Boeckel et al., 2015). 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 (Van
Boeckel et al., 2015). 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 mortality rates imposed by MDR infections? These extremely
worrying trends dictate the need for global and coordinated actions to prevent 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.

33

Table 1. History of discovery of main antimicrobial classes.

Arsphenamines
1910

-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

34

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