1

1. What is an Antibiotic?
Joan Wennstrom Bennett
Pages: 1-18.
DOI: https://doi.org/10.21775/9781908230546.01
The word 'antibiotic' was originally used in the English language as an adjective. In 1947, Selman A.
Waksman published a definition of 'antibiotic' as a noun: "An antibiotic is a chemical substance, produced
by micro-organisms, which has the capacity to inhibit the growth of and even to destroy bacteria and other
micro-organisms." The clinical efficacy of penicillin and streptomycin brought public attention to this group
of life-saving drugs and the word "antibiotic" soon became commonplace in scientific and ordinary
language. Waksman stressed that antibiotics were not only antimicrobial in action but also that they were
products of microbial metabolism. He excluded compounds made by plants, animals or synthetic chemists.
Contemporary usage makes no such distinction. Because most of the early antibiotics were effective only
against bacteria, and because responsible health care workers warned patients against the asking for
antibiotics to treat viral infections, nowadays 'antibiotic' is often used as a synonym for 'antibacterial' in
order to simplify communication. Curiously, Waksman's original definition and most of the energy he
subsequently devoted to defending his definition rarely included mention of the single most important
property of a good antibiotic, namely that it does not harm the host. Many of the currently published
definitions continue in the Waksman tradition and focus on the antimicrobial activity of the compounds, not
on their selective action. The published literature can be an important resource in the search for new
efficacious compounds with antimicrobial action. Thus, it is more important than ever to have an
understanding of how the word 'antibiotic' is used in different contexts so as to guide contemporary
information scientists to mine the vast scientific and patent literature.
2. Main Applications of Antibiotics
Biao Ren, Pei Huang, Jingyu Zhang, Wenni He, Jianying Han, Xueting Liu and Lixin Zhang
Pages: 19-48.
DOI: https://doi.org/10.21775/9781908230546.02
Antibiotics have been developed for more than 80 years since the investigation of the sulfonamides and β-
lactams in 1930s. Meanwhile, the pathogenic bacteria developed resistance to antibiotics rapidly and have
caused urgent threat to public health. In addition, many antibiotics are used commercially, or are potentially
useful, in medicine for activities other than their antimicrobial action. They are used as antitumor agents,
enzyme inhibitors including powerful hypocholesterolemic agents, immunosuppressive agents, and anti-
migraine agents, etc. The purpose of this chapter is to focus on the application of anti-bacterials,
antifungals, and anti-cancers with their clinical use to date, including the development history, side effects,
and etc. The antibiotics summarized herein were classified by their uses, structure types, and molecular
mechanisms.
3. Microorganisms Producing Antibiotics
János Bérdy
Pages: 49-64.
DOI: https://doi.org/10.21775/9781908230546.03
The meaning of the definition of antibiotics, that is the bioactive secondary microbial metabolites, and
specific features of the history of antibiotic research in the last eighty years shows continuous changing.
The real role of the microbial metabolites in the various life processes in the Earth is far to be totally
explored. Their importance, over the antibiotic effect, seems to be more significant than in was believed.
They may be general regulatory and signally compounds in the most life processes and in the environment.

The main producers of the microbial metabolites, the actinobacteria, fungi and other filamentous bacteria,
represent inexhaustible sources for the future. The connecting and increasing taxonomic, chemical and
biodiversities of microbial metabolites certainly will give numerous new leads and drugs and other products
not only for the chemotherapy but in other fields of human therapy and also for the agriculture to cure and
feed the increasing population.

The numbers of known and possible secondary metabolite producing microorganisms, the produced new
chemical compounds and their extremely wide range of bioactivities are discussed in details. Several new
trends of the research, the full exploration of the living world of oceans and the discovery of endophytic
microbes are also presented.

4. The Need for New Antibiotics

Arnold L. Demain and Sergio Sanchez
Pages: 65-82.
DOI: https://doi.org/10.21775/9781908230546.04
The large amounts of antibiotics used in human therapy, as well as those used for farm animals and
aquaculture, have resulted in the selection of pathogenic bacteria resistant to multiple drugs. New
antibiotics are continuously required to combat antibiotic-resistant bacteria and pathogenic yeast. Such
resistance increasingly limits the effectiveness of current antimicrobial drugs. The problem is not just
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antibiotic resistance, but also the appearance of an increasing number of multidrug-resistant pathogenic
bacteria. Resistant bacteria were detected in hospitals and nosocomial infections have become a major
problem. Staphylococcus aureus is responsible for half of hospital-acquired infections and causes deaths
of many people around the world. Besides the problem of antibiotic-resistance, new families of antibiotics
are needed to enter the marketplace at regular intervals to face new diseases caused by evolving
pathogens. At least 30 new diseases emerged in the 1980s and 1990s and they are growing in incidence.
Also important are reemerging diseases such as influenza and hepatitis B. Due to the movement of the
pharmaceutical industry away from natural products, especially antibiotics, the number of drug approvals in
recent years has drastically dropped. However, antimicrobial pharmaceuticals are still big business and the
search for new drugs must not be stopped. New screening approaches, including the search for novel
targets and exploration of non-conventional places as sources of the producer microorganisms, are
needed. In addition, metagenomic and genome- mining techniques have shown strong potential for
discovery of new antibiotics. What is needed is a move back by the large companies to rational drug design
and the use of more focused, more drug-like, compound libraries. In addition, it is desirable that small
companies and academics, either in an independent manner or organized as biotechnology/university
groups, increase their participation in a worldwide effort for new antibiotic discovery.
5. Tackling Antibiotic Resistance
Jaroslav Spizek and Vladimir Havlicek
Pages: 83-94.
DOI: https://doi.org/10.21775/9781908230546.05
Resistance to antibiotics and other antimicrobial compounds permanently increases and it appears that the
struggle against antibiotic resistance is a war we can never win. The strength of the immense numbers of
microorganisms appears to overpower our drugs. However, there are hopes and chances to at least
improve the situation. In the present review we want to discuss certain steps to be used to tackle antibiotic
resistance including: 1. Preparation of new vaccines against resistant bacterial strains, 2. Search for new
antibiotics in both traditional and non-traditional sources 3. Search for genes specifying biosynthesis of
antibiotics, 4. Use of forgotten natural compounds and their transformation, and 5. Search for new antibiotic
targets. We want to devote a special attention to the search for new compounds that would inhibit the
currently antibiotic resistant pathogenic bacteria.
6. Eradication of Dormant Pathogens
Kim Lewis, Brian Conlon and Michael LaFleur
Pages: 95-108.
DOI: https://doi.org/10.21775/9781908230546.06
Persisters are specialized survivor cells that protect bacterial and fungal populations from killing by
antibiotics. Persisters are dormant phenotypic variants of regular cells rather than mutants. Most
microbicidal antibiotics kill by corrupting their targets into producing toxic products; tolerance to antibiotics
follows when targets are inactive. Mechanisms of persister formation are redundant, making it difficult to
eradicate these cells. In Escherichia coli, toxins RelE and MazF cause dormancy by degrading mRNA;
HipA inhibits translation by phosphorylating glutamyl tRNA synthase; and TisB forms an anion channel in
the membrane, leading to a decrease in proton motive force (pmf) and ATP levels. Prolonged treatment of
chronic infections with antibiotics selects for hip mutants that produce more persister cells. Eradication of
tolerant persisters is a serious challenge. Existing antibiotics were developed to kill rapidly growing cells
and have limited activity against dormant persisters. A number of compounds were recently described that
have a capability of killing persisters. A potentiator of azoles, AC17, sterilizes a biofilm of  Candida albicans.
Prodrugs are converted into generally reactive compounds with bacteria-specific enzymes and kill growing
and dormant cells. Lassomycin activates the ATPase of the ClpP1P2C1 protease of Mycobacterium
tuberculosis, and kills persisters. Acyldepsipeptide (ADEP4) activates the ClpP protease, forcing the cell to
self-digest, and kills both growing cells and persisters. These findings suggest a path towards developing
sterilizing antibiotics.
7. Toxicity of Antibacterial Drugs
Steven J. Projan
Pages: 109-112.
DOI: https://doi.org/10.21775/9781908230546.07
Therapeutic antibacterial drugs are considered among the safest of pharmaceuticals but this was not
always the case. Indeed prior to the discovery of penicillin and, subsequently, other antibiotics, the safety
profile of antibacterial drugs more closely resembled that of today's cytotoxic, chemotherapeutic agents
used in oncology with narrow therapeutic windows and considerable side effects. Today's antibiotics are, in
fact, safe by design. Where agents have defined toxicities (e.g. photosensitivity induced by
fluoroquinolones) they are usually class effects and, rather than "idiosyncratic" are more frequently
predictable based on pharmacokinetics and tissue distribution. As newer antibacterial drugs are being
designed to be more "pathogen specific" the expectation is that these future drugs will have even better
safety profiles than today's therapeutics.
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The common perception of antibacterial drugs is that they are very safe, very useful and very important
therapeutic agents, indeed the safety and tolerability of antibacterials are, in general are among the best of
all prescribed drugs. This is not a matter of chance and it was not always the case. In 1908 Paul Ehrlich
shared the Novel Prize for Medicine or Physiology (with Ilya Metchnikoff) for his work on
immunotherapeutics (indeed the first Nobel Prize in that category went to Emil von Behring, also for
immunotherapy) but Ehrlich was unhappy both with the efficacy of immunotherapeutics as well as their
safety (e.g. "serum sickness"). He embarked on a bona fide medicinal chemistry/drug discovery campaign
to find novel organic molecules based on arsenical compounds that were active versus trypanosomes and
spirochetes. It should be noted that at the turn of the twentieth century mercury was still being used as
treatment for syphilis, a bacterial infection caused by Treponema pallidum. Even today, mercury toxicity
remains an important issue. The compound that Ehrlich's group eventually discovered, arsphenamine
("606") became known as Salvarsan and was both more effective and far safer than mercury treatment (not
to mention less expensive) but was not without its own safety and tolerability issues (which are a subject of
controversy even today) (Baumler,1984). Eventually arsphenamine was supplanted by penicillin, where
even a single, intramuscular dose was found to be effective in the early stages of the disease with a
significantly better safety profile. It should be realized that today's antibacterial drugs are safe not as a
matter of chance but by design; the result of decades of microbial research, the development of in vitro and
animal models of infection, brute force science and inventive medicinal chemistry, and careful (as well as
some careless) clinical research resulting in the successful treatment of hundreds of millions (if not billions)
of people.

8. Overuse of Antibiotics: Non-medical Applications

Nelson Kardos
Pages: 113-146.
DOI: https://doi.org/10.21775/9781908230546.08
The decreasing effectiveness of antibiotics in treating common infections results from the spread of
antimicrobial resistance (AMR), and is building up to become an epic global public health crisis. Extended
periods of antibiotic overuse and misuse since their introduction have applied strong selective pressure
towards high level AMR and multiple drug resistance (MDR), rendering entire classes of antibiotics
ineffective. The primary driving force for this global AMR pandemic is the widespread misuse and overuse
of antibiotics, in both medical and non-medical applications. The introduction of every antibiotic product has
been closely followed by emerging resistance to that antibiotic. Levels of antibiotic consumption correlate
with levels of AMR. Antibiotics have been misused in all of their applications, including:

Hospital and outpatient use by physicians through unnecessary, indiscriminate or incorrect prescribing
By patients, through incorrect dosing and course durations
Large scale use in agriculture for disease treatment, prophylaxis and growth promotion in animal
husbandry and food production

These actions not only have provoked the emergence of resistant microbes, but also have provided optimal
environments for the spread of and selection of resistance determinants. It has been established in many
countries that the levels of antibiotic consumption consistently correlate with levels of antibiotic resistance
(i.e. the more antibiotics are being used in a population, the more resistance to antibiotics there will be in
bacteria responsible for infections in that population). The increase in resistance from overuse of antibiotics
in turn leads to cross transmission of AMR microbes between humans, between animals and between
humans and animals and the environment. Almost two million Americans per year develop hospital
acquired infections (HAI), resulting in 99,000 deaths per year. The vast majority of these HAI related deaths
are due to AMR infections. Based on studies of the costs of infections caused by antibiotic resistant
pathogens vs. antibiotic susceptible pathogens, the annual cost to the US health system of antibiotic
resistant infections is to billion, and 8 million additional hospital days. This chapter will focus on the overuse
of antibiotics through non- medical applications; by their extensive use in animal agriculture & aquaculture
and their effect as environmental contaminants on land and water systems. These non-human medical
applications are a primary cause of AMR and ultimately impact negatively on human health.

9. Antibiotics for Emerging and Re-emerging Diseases

Kazuro Shiomi and Satoshi Ōmura
Pages: 147-174.
DOI: https://doi.org/10.21775/9781908230546.09
Emerging and re-emerging infectious diseases are global problems, and a constant supply of new
antibiotics is essential if we are to combat these diseases successfully. Among antibiotics currently used
against these diseases, antiparasite antibiotics are to the fore and are the major focus of this chapter. For
example, tetracyclines are used against malaria, acetylspiramycin and clindamycin are used for
toxoplasmosis, amphotericin B is used for leishmaniasis, and trichomycin is deployed against
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trichomoniasis. Nitroimidazole compounds used for various protozoiasis are analogs of azomycin.
Ivermectin is a great nematocide, used for onchocerciasis, lymphatic filariasis, and strongyloidiasis.
Paromomycin is used for the treatment of cestodiasis. Recent research for new antiparasite antibiotics is
also described. Viral diseases represent a significant and growing threat among the major emerging and
re-emerging infectious diseases and studies in this line of research, particularly on antibiotics active against
HIV and influenza virus, are briefly covered. Even within the human body, our own essential microbial flora
can pose a considerable and extremely complicated threat, such as diarrheagenic  Escherichia
coli (O157:H7) which is responsible for an emerging disease. Fortunately, recent research has uncovered a
new type of antibiotic that only inhibits pathogenicity and does not affect the growth of pathogenic  E. coli.
The new type of antibiotic is expected to avoid some problems of conventional antibiotics: development of
resistant strains, expression of various toxins, and disruption of normal microbial flora.
10. Endophytes as a Potential Source of New Antibiotics
Silvia Guzmán-Trampe, Karol Rodríguez-Peña, Allan Espinosa-Gómez, Rosa E. Sánchez-Fernández,
Martha L. Macías-Rubalcava, Luis B. Flores-Cotera and Sergio Sánchez
Pages: 175-204.
DOI: https://doi.org/10.21775/9781908230546.10
Antibiotics are useful compounds for treatment of human, farm animal and aquaculture infections.
However, due to resistance development of pathogenic microbes to most of the useful antibiotics, there is a
continuous necessity for new and powerful anti-infective compounds. This situation encourages the search
for new alternatives for the isolation of new compounds with antimicrobial activity. Because of their
proficiency in producing secondary metabolites with therapeutic properties, plants have attracted attention
since ancient times. Recently, plant endophytic microorganisms have been also shown to be an important
and novel source of natural bioactive products with antimicrobial, antiviral, antitumor, antiparasitic, and
agricultural activities. Endophytes commonly live associated to the plant vascular tissues, without causing
any apparent damage to their host or symptoms of disease. The bioactive compounds they produce,
usually vary depending on the plant host taxonomy and forest type. Fungi and actinomycetes have been
the main source of new bioactive natural products from endophytes. Occasionally, endophytes can
synthesize the same metabolites produced by the host plant. This chapter mainly reviews the progress that
has been achieved on the production, by endophytic microbes, of the same or similar bioactive compounds
originated from their host plants, as well as other secondary metabolites apparently not produced by the
plant, including antituberculosis and antiparasitic compounds. Furthermore, the potential agricultural uses
of endophytic compounds as antifungal, nematicidal, antiviral, insecticidal and phytotoxic activities, is also
reviewed. Finally, we mention some examples of new compounds with antimicrobial properties chemically
derived from natural products produced by endophytes.
11. Antibiotics from Micro-organisms from Hot springs/Geysers
Girish B. Mahajan
Pages: 205-212.
DOI: https://doi.org/10.21775/9781908230546.11
Nature has provided mankind with abundant resources in the form of bioactive compounds which have
been isolated from microbial resources. Novel natural products can have many innumerable potential uses,
especially in the area of new drug discovery. Extensive research in this field has reported several terrestrial
mesophilic sites. The marine environment has recently evinced more interest, and several thousands of
novel bioactive compounds have been identified from various marine microorganisms. The constant need
for new leads from the healthcare sector has sparked off a relentless quest for novel compounds. A
difference in the habitat of the microorganisms yields different types of microorganisms, thus resulting in
some variation in the types of compounds obtained from them. Physically and chemically extreme
ecological units on the globe harbor special groups of microbes which are genetically well acclimatized to
the stress conditions, and their adaptive ability makes them unique producers of different classes of
compounds. Hot springs or geysers are such ecological niches, which have been studied mainly from their
biodiversity point of view. There have been occasional reports of their harboring a huge cache of bioactive
compounds from the drug discovery perspectives. In this article, we have tried to review present some such
ecological niches.
12. New Sources of Antibiotics: Caves
Naowarat Cheeptham and Cesareo Saiz-Jimenez
Pages: 213-228.
DOI: https://doi.org/10.21775/9781908230546.12
Caves are regarded as extreme habitats according to their unique and harsh conditions for microbial life.
Though demanding, these irreplaceable habitats have demonstrated to support a great diversity of
microbial communities that are believed to hold great promises as new sources of antibiotics and
industrially relevant compounds. This chapter highlights recent findings that convincingly solidify the
concept that caves are potentially homes to novel and rare microorganisms and tomorrow's antibiotics.
13. Animal Venoms as Natural Sources of Antimicrobials
R. Perumal Samy, S. Satyanarayanajois, O. L. Franco, B. G. Stiles and P. Gopalakrishnakone
Pages: 229-248.
DOI: https://doi.org/10.21775/9781908230546.13
5

A number of naturally occurring proteins/peptides exert antimicrobial activities reported throughout the
literature, of which snake venoms (SV) represent a vast natural source of protein/peptides not thoroughly
explored to date. Snake venoms represent rich sources of bioactive compounds, which are produced by
venom glands located around the snake's jawbone. In this review, we focus more on the basis of
antimicrobial potential within SV and further need to search for novel antibiotic prototypes. Several
enzymes [i.e. phospholipase A2 (PLA2) (these are part of PLA22) L-amino acid oxidase and
metalloproteinase], as well as antimicrobial peptides (AMPs) such as cathelicidine and defensin, have been
isolated by various groups from SV. Antimicrobial proteins/peptides work in various ways that include
hydrolyzing phospholipids on the bacterial surface. The presence of unusual amino acids and structure
motifs in AMPs confer unique structural properties that contribute their specific mode of action. The ability
of these active AMPs to act as multifunctional effectors such as signaling molecules and antibacterial
agents makes them interesting candidates for structural and biological studies for prophylactic and
therapeutic applications. In this review, we focus on the diversity and antimicrobial activities of various SV-
derived molecules potentially useful as drug candidates for the pharmaceutical industry.
14. New Targets for Antibacterial Compounds
Lynn L. Silver
Pages: 249-274.
DOI: https://doi.org/10.21775/9781908230546.14
Resistance to antibacterials underwent a noticeable rise starting in the mid-1980's, at a time when natural
product screening for antibacterial antibiotics had become less productive. The advent of genome
sequencing of bacteria, starting in 1995 seemed to provide an answer to the resistance problem: find new
gene products to target in order to find antibacterial agents that were different from previous classes and
unlikely to be cross-resistant with them. This plan relied on the assumption that the limitation to discovery
was a lack of novel targets. As the search for antibacterials over the past twenty years has been largely
directed toward finding inhibitors of novel targets, and that search has been largely unproductive, it seems
likely that the assumption that targets are rate limiting is wrong. This chapter will discuss the characteristics
that define good targets, with an emphasis on recognizing the potential for rapid resistance development
with single-gene targets. Until it is robustly demonstrated that combinations of single-targeted agents can
prevent or retard resistance development (as is seen with tuberculosis, HIV and HCV) and a regulatory
pathway is established to develop such combinations, it may be that we will have to depend on the
successful targets that have already been found and exploited.
15. Novel Antimicrobial and other Bioactive Metabolites Obtained from Silent Gene Clusters
Juan F. Martín and Paloma Liras
Pages: 275-292.
DOI: https://doi.org/10.21775/9781908230546.15
Hundreds of secondary metabolite gene clusters have been found in the genome sequence of filamentous
fungi, Streptomyces species and some rare actinomycetes (20 to 50 clusters per genome). However, the
number of secondary metabolites found in the culture broths of each strain is much lower than the number
of gene clusters in that particular strain. Many of the sequenced gene clusters are silent or very poorly
expressed, and there is a high untapped potential for the discovery of novel antibiotics or other bioactive
products. Classical strategies to trigger production of secondary metabolites rely on the use of nutritional
stressing conditions such as phosphate starvation or ammonium limitation, and the addition of phosphate-
precipitating or ammonium-trapping agents leads to formation of new products. Metal toxicity also triggers
the production of novel secondary metabolites in some Streptomyces strains. Modification of the rpsL (for
the ribosomal protein S12) or the rpoB (for the RNA polymerase β subunit) genes enhance the expression
of silent or poorly expressed secondary metabolite gene clusters in several Streptomyces species. Addition
of antibiotic biosynthesis "remodeling compounds" re-directs the metabolic flux to obtain new antibiotics.
Modern strategies to awaken sleeping clusters include the modification of wide domain regulators that
control related or even disparate pathways. Alteration of butyrolactone receptor proteins or of an
oligopeptide-binding protein results also in awakening of silent gene clusters in some producer strains. Co-
cultivation of Streptomyces with other bacteria or fungi, involving contact between cells, frequently triggers
silent gene clusters. The potential of these strategies to trigger the expression of silent clusters in poorly
studied actinobacteria other than Streptomyces, is very high.

In fungi, rearrangements of the chromatin structure by either directed mutations of some genes or by the
use of "chromatin modifiers", has provided several new compounds in each of the tested fungi. Particularly,
deletion or overexpression of the laeA gene that influences chromatin rearrangement, modifies the
transcription of some low-expression gene clusters and awakens the expression of some silent clusters
providing new compounds. Expression of the laeA gene is increased by the fungal autoinducer 1,3-
diaminopropane, what may trigger some silent clusters.

Examples of new molecules synthesized by the enzyme encoded by different silent or "near-silent" gene
clusters are provided in this article. Most of the novel products observed by HPLC or by bioassays still
remain to be characterized chemically.
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16. Combinatorial Biosynthesis for Antibiotic Discovery

Sung Ryeol Park and Yeo Joon Yoon
Pages: 293-320.
DOI: https://doi.org/10.21775/9781908230546.16
The rapid and increasing prevalence of antibiotic-resistant pathogenic microorganisms has heightened the
need for development of novel antibiotics. Natural products have traditionally been a prolific source of
therapeutic agents for infectious diseases and other illnesses. However, as searching for new antibiotics
with desired properties from natural products has become increasingly challenging, researchers have
turned towards a genetic approach known as combinatorial biosynthesis to generate novel bioactive
compounds for antibiotic discovery. In this chapter, we will review the past and current attempts and
achievements to discover potentially novel antibiotic derivatives through combinatorial biosynthesis, and
discuss its role and importance as well as its challenges, giving insights into the future trends and
possibilities. In addition, multiple approaches, including heterologous expression and in vitro
glycorandomization, coupled with the combinatorial biosynthesis technique will be described. Moreover,
although we will focus on antibacterial compounds and their derivatives, several other related compounds
will be mentioned to enlighten the concept of combinatorial biosynthesis.
17. Lantibiotics and Other Antibacterial Peptides
Margherita Sosio and Stefano Donadio
Pages: 321-330.
DOI: https://doi.org/10.21775/9781908230546.17
Lantibiotics and other ribosomally synthesized peptides have attracted increasing attention in the search for
new chemical classes of antibacterial agents effective against multidrug-resistant pathogens. Several
factors have probably contributed to this resurgent interest. Among them, the realization that many different
classes of ribosomally synthesized peptides are produced by almost all taxa of bacteria; that lantibiotics,
being ribosomally synthesized, are amenable to the generation of analogs by codon substitutions in the
structural gene; and that, by binding to biosynthetic intermediates and not directly to enzymes, resistance in
bacterial pathogens cannot be simply acquired by mutations in the target enzymes. In this chapter, we will
review the chemistry, biosynthesis, occurrence and mechanism of action of lanthipeptides, with particular
focus on lantibiotics. We will also present three lantibiotics that are currently under advanced preclinical or
early clinical development, as well as some recently discovered compounds which represent improved
variants of known lantibiotics.
18. Antiviral Compounds of Natural Origin
P. Veiga-Crespo, M. Viñas and Tomas Gonzalez Villa
Pages: 331-344.
DOI: https://doi.org/10.21775/9781908230546.18
A great variety of plant-and-medicinal herb-derived active principles have been traditionally known by the
Natural Medicine of many civilizations. Recent advances in Molecular Biology have allowed us to
characterize those active principles, to understand their mode of action and finally to include many of these
compounds in the arsenal of antiviral drugs used by Western medicine. The higher number of resistant-
strains both in the bacterial and viral worlds makes mandatory the continuous search for new active
principles to treat diseases. Many of the natural remedies used in medicine are now being characterized
and will facility their use as regular chemotherapeutics.
19. New Compounds with Antibacterial Activity
P. Veiga-Crespo, A. Sánchez-Pérez, D. Piso and Tomas Gonzalez Villa
Pages: 345-374.
DOI: https://doi.org/10.21775/9781908230546.19
Infections caused by pathogenic microorganisms are among the major causes of global mortality and
morbidity. The discovery and use of antibiotics revolutionized medicine as they constituted not only the first
real therapeutic weapon against bacteria but also the possibility of eradication of bacterial disease in
humans. However, the combination of antibiotic misuse and bacterial natural evolution rendered them less
efective and resulted in the phenomenon known as antibiotic resistance. Although it is currently mandatory
to search for new therapies, antibiotics still offer many potential uses, these range from enzybiotics to new
nanotechnology-based delivery systems.
20. Use of Antibiotic Core Structures to Generate New and Useful Macrolide Antibiotics
Prabhavathi Fernandes
Pages: 375-394.
DOI: https://doi.org/10.21775/9781908230546.20
Macrolides, such as erythromycin, are safe and effective antibiotics that are broadly used in adults and
children. Clarithromycin and azithromycin were introduced in the 1990s and became popular because of
improved gastrointestinal tolerability and pharmacokinetics but they exhibit cross resistance with
erythromycin. Intense efforts in many pharmaceutical companies led to the third-generation macrolide,
telithromycin, a 3-keto aglycone of clarithromycin with an extended 11, 12-carbamate side chain.
Telithromycin was invented using two lessons learned from older macrolides:(i) additional side chains on
the macrolide ring, as found on 16-membered macrolides, can gain activity against resistant organisms,
and (ii) an aglycone with a keto group as noted in picromycin, instead of erythromycin's cladinose can
7

retain antibacterial activity. Although active against drug-resistant bacteria, telithromycin failed in the clinic
due to serious adverse events. Solithromycin is a fourth generation macrolide, a fluoroketolide, in late stage
development that is differentiated from telithromycin in lacking the latter's pyridine containing side chain,
which interacts with human nicotinic acetylcholine receptors to produce treatment-limiting side effects, and
in having a third binding region in the bacterial ribosome to help overcome resistance. Solithromycin is in
late-stage clinical development. Molecular mode of action studies could lead to even more potent
molecules in the future, perhaps with uses beyond antiinfectives.
21. Antibiotics in the Pipeline
Hyunjun Park and Michael Thomas
Pages: 395-416.
DOI: https://doi.org/10.21775/9781908230546.21
The enormous success of using antibiotics to save lives is being challenged by the steady evolution of
resistance to these antibiotics by the targeted bacteria. This resistance has led to predictions that we will
soon be returning to the pre-antibiotic era whereby even the most minor infection has the potential to have
severe consequences on the infected person. Fortunately, there has been a steady increase in the efforts
to combat this rise in antibiotic resistance. This chapter discusses antibiotics for treating bacterial infections
that were in the clinical pipeline at the beginning of 2014. While a list of the drugs that have recently been
approved for clinical use or are in various phases of clinical trials is provided, a select few are highlighted in
more detail to show how drug development itself is evolving to generate the next generation of antibiotics
so the pre-antibiotic era stays in the past.