Chemistry of Antibiotics and Related Drugs (2nd Edition) Bhattacharjee

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Mrinal K. Bhattacharjee

Chemistry
of Antibiotics
and Related
Drugs
Second Edition

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Chemistry of Antibiotics and Related Drugs (2nd Edition) Bhattacharjee
Chemistry of Antibiotics and Related Drugs

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Chemistry of Antibiotics and Related Drugs (2nd Edition) Bhattacharjee
Mrinal K. Bhattacharjee

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Chemistry of Antibiotics
and Related Drugs
Second Edition

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Chemistry of Antibiotics and Related Drugs (2nd Edition) Bhattacharjee
Mrinal K. Bhattacharjee
Department of Chemistry and Biochemistry
Long Island University
Brooklyn, NY, USA

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ISBN 978-3-031-07581-0 ISBN 978-3-031-07582-7 (eBook)

https://doi.org/10.1007/978-3-031-07582-7

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Chemistry of Antibiotics and Related Drugs (2nd Edition) Bhattacharjee

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This book is dedicated to my wife Nayana and

daughter Neha

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Chemistry of Antibiotics and Related Drugs (2nd Edition) Bhattacharjee
Preface

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Millions of lives have been saved by antibiotics since they were first discovered
more than 90 years ago. This book discusses the various classes of antibiotics and
their mechanisms of action. For the first few decades, antibiotics had a remarkable
success, encouraged by which in 1969, the then-US Surgeon General, William
Stewart testified before Congress that it was “time to close the book on infectious
disease.” Today we know how premature that statement was. Today, more than five
decades later, infectious disease still remains the leading cause of death worldwide
and ranks among the top ten causes of death in the USA. The main reason for all
these is that bacteria are increasingly becoming resistant to antibiotics. Mechanisms
by which bacteria develop resistance to antibiotics are also discussed here. Because
of the increasing antimicrobial resistance, it is of utmost importance to discover new
antibiotics. Alternative strategies for discovering new antibiotics are presented. The
World Health Organization has recognized the threat of growing antimicrobial
resistance and has adopted a Global Action Plan to combat the threat. This plan
and similar plans of member countries as well as Stewardship Programs adopted by
agencies at local levels are also discussed.
This book has been written keeping the student in mind. The main focus is to
explain how antibiotics work in curing infectious diseases and how resistance
develops to the antibiotics such that they do not work anymore. A background in
Biochemistry is needed to understand the mechanism of action of the antibiotics.
However, any background information that is needed is discussed in the book. So it
will not be necessary for the student to consult any separate biochemistry textbook,
or register for a separate course in biochemistry, in order to understand the theory of
antibiotics. However, the discussion of biochemistry in this book is not meant to be
complete. The only information presented is what is relevant to the understanding of
antibiotics.
There are many other important aspects of antibiotics that are studied by doctors,
pharmacists, and scientists but are beyond the scope of this book. Some of these
aspects are briefly mentioned here but will not be discussed in much detail in the
book.

vii

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 viii Preface
Chemistry of Antibiotics and Related Drugs (2nd Edition) Bhattacharjee
1. Dosage, formulation, bioavailability, and biostability are important aspects for
effective use of antibiotics. These ensure that the antibiotic will be delivered
specifically to diseased site in the right amount and for the required duration.
Dose depends on how much of the antibiotic is absorbed from the digestive
system, how stable it is, how much enters the cells, the distribution of the drug in
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various tissues, and many other factors. However, discussions of these aspects are
beyond the scope of this book.
2. All antibiotics do not work for all infections. Also, antibiotics have various side
effects and may interact with other drugs to give unwanted effects. Information
needed to decide about which antibiotic to prescribe for which infection is beyond
the scope of this book.
All antibiotics will be referred to here by their common names such as penicillin,
tetracycline, erythromycin, etc., even though many of these antibiotics have other
brand names given by the manufacturers. There are also various derivatives with
altered but similar activities for many of these antibiotics. Not all of these names are
included in this book. All antibiotics will also have a systematic name based on
IUPAC nomenclature of organic compounds. Those names will be mentioned for the
simple molecules but not for those with complex structures.

Brooklyn, NY, USA Mrinal K. Bhattacharjee

April 2022

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Chemistry of Antibiotics and Related Drugs (2nd Edition) Bhattacharjee
Contents

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1 Introduction to Antibiotics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
1.1 Definition of Antibiotics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
1.2 History of Antibiotics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
1.3 The Ideal Antibiotic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
1.4 Sources of Antibiotics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
1.5 Discovery of Modern Antibiotics . . . . . . . . . . . . . . . . . . . . . . . 7
1.6 Classification of Antibiotics . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
1.7 Background Biochemistry Information . . . . . . . . . . . . . . . . . . . 13
1.7.1 Enzymes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
1.7.2 Enzyme Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . 14
1.7.3 Enzyme Mechanisms . . . . . . . . . . . . . . . . . . . . . . . . 15
1.7.4 Metabolism and Metabolic Pathways . . . . . . . . . . . . . 18
1.7.5 Thermodynamics of Metabolic Pathways . . . . . . . . . . 19
1.7.6 High-Energy Compounds . . . . . . . . . . . . . . . . . . . . . 21
1.7.7 Metabolically Irreversible and Near-Equilibrium
Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
1.7.8 Membrane Transport . . . . . . . . . . . . . . . . . . . . . . . . 26
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
2 Development of Resistance to Antibiotics . . . . . . . . . . . . . . . . . . . . 29
2.1 Antibiotics Are No Longer Considered to Be Miracle Drugs . . . 29
2.2 Detection of Antibiotic Resistance . . . . . . . . . . . . . . . . . . . . . . 30
2.3 Classification of Antibiotic Resistance . . . . . . . . . . . . . . . . . . . 31
2.4 Resistance Development by Point Mutations . . . . . . . . . . . . . . . 31
2.5 Selection for Resistance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33
2.6 Resistance Development by Resistance Gene Acquisition . . . . . 35
2.7 Mechanism of Antimicrobial Resistance . . . . . . . . . . . . . . . . . . 38
2.8 Synthetic Antibiotics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
2.9 Alternative Approaches for Studying Antibiotics . . . . . . . . . . . . 42
2.10 Antibiotic Use in Animals . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44

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 x Contents
Chemistry of Antibiotics and Related Drugs (2nd Edition) Bhattacharjee
2.10.1 Therapeutic Use . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44
2.10.2 Subtherapeutic Use . . . . . . . . . . . . . . . . . . . . . . . . . . 45
2.11 Prevention of Antibiotic Resistance Development . . . . . . . . . . . 50
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51
3 Antibiotics That Inhibit Cell Wall Synthesis . . . . . . . . . . . . . . . . . . 55
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3.1 Background Biochemistry Information . . . . . . . . . . . . . . . . . . . 55
3.1.1 Carbohydrates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55
3.1.2 Molecular Structure of Bacterial Cell Wall . . . . . . . . . 58
3.2 Biosynthesis of Peptidoglycan of the Cell Wall . . . . . . . . . . . . . 58
3.2.1 Stage 1: The Cytosolic Phase of Synthesis . . . . . . . . . 59
3.2.2 Stage 2: The Membrane Phase of Synthesis . . . . . . . . 62
3.2.3 Stage 3: The Cell Wall Phase of Synthesis . . . . . . . . . 64
3.3 Antibiotics That Inhibit Cell Wall Biosynthesis . . . . . . . . . . . . . 67
3.3.1 Antibiotics Targeting the Cytosolic Phase
of Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67
3.3.2 Antibiotics Targeting the Cell Wall Phase
of Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70
3.3.3 Antibiotics Targeting the Membrane Phase
of Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91
3.3.4 Teixobactin, A Newly Discovered Antibiotic . . . . . . . 102
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103
4 Antimetabolites: Antibiotics That Inhibit Nucleotide Synthesis . . . . 109
4.1 Antimetabolites . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109
4.2 Background Biochemistry Information: Folic Acid . . . . . . . . . . 110
4.3 Antibiotics That Inhibit Folate Metabolism . . . . . . . . . . . . . . . . 112
4.3.1 Sulfa Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113
4.3.2 Mechanism of Action of Sulfonamides . . . . . . . . . . . 113
4.3.3 Negative Aspects of Sulfonamides . . . . . . . . . . . . . . . 115
4.3.4 Non-sulfonamide Antimetabolites of Folic Acid . . . . . 115
4.3.5 Antimetabolites as Dihydrofolate Reductase
(DHFR) Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . 117
4.3.6 Antimetabolites as Antibacterial, Antimalarial,
and Anticancer Agents . . . . . . . . . . . . . . . . . . . . . . . 118
4.3.7 Thymidylate Synthase Inhibitor: 5-Fluorouracil . . . . . 120
4.3.8 Other Antimetabolites: Azaserine and
Diazo-Oxo-Norleucine . . . . . . . . . . . . . . . . . . . . . . . 122
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123
5 Antibiotics That Inhibit Nucleic Acid Synthesis . . . . . . . . . . . . . . . . 125
5.1 Background Biochemistry Information . . . . . . . . . . . . . . . . . . . 125
5.1.1 Structure of Nucleotides . . . . . . . . . . . . . . . . . . . . . . 125
5.1.2 Watson–Crick Model of DNA . . . . . . . . . . . . . . . . . . 126
5.1.3 Superhelical Structure of DNA . . . . . . . . . . . . . . . . . 128

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 Contents xi
Chemistry of Antibiotics and Related Drugs (2nd Edition) Bhattacharjee
5.1.4 DNA Replication . . . . . . . . . . . . . . . . . . . . . . . . . . . 129
5.2
Intercalators as Antibiotics . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131
5.3
Inhibitors of DNA Gyrase: Quinolones . . . . . . . . . . . . . . . . . . . 132
5.3.1 Mechanism of Resistance to Quinolones . . . . . . . . . . 136
5.4 Nitroheterocyclic Aromatic Compounds as Antibiotics . . . . . . . 138
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5.4.1 Nitroimidazoles: Antibiotics That Cleave DNA . . . . . 138
5.4.2 Nitrofurans: Multiple Possible Mechanisms
of Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141
5.5 RNA Synthesis: Background Biochemistry Information . . . . . . . 142
5.6 Rifamycins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 143
5.7 Actinomycin D (Dactinomycin) . . . . . . . . . . . . . . . . . . . . . . . . 145
5.8 Fidaxomicin: A New Antibiotic with a New Target . . . . . . . . . . 145
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145
6 Antibiotics That Inhibit Protein Synthesis . . . . . . . . . . . . . . . . . . . . 149
6.1 Protein Synthesis: Background Biochemistry Information . . . . . 149
6.2 Antibiotics That Inhibit Protein Synthesis . . . . . . . . . . . . . . . . . 155
6.2.1 Puromycin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 156
6.2.2 Aminoglycosides . . . . . . . . . . . . . . . . . . . . . . . . . . . 157
6.2.3 Resistance to Aminoglycosides . . . . . . . . . . . . . . . . . 159
6.2.4 Tetracyclines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161
6.2.5 Chloramphenicol . . . . . . . . . . . . . . . . . . . . . . . . . . . 163
6.2.6 The MLS Group of Antibiotics . . . . . . . . . . . . . . . . . 165
6.2.7 Two Truly New Antibiotics . . . . . . . . . . . . . . . . . . . . 168
6.2.8 Protein Synthesis Antibiotics with Unusual
Mechanisms of Action . . . . . . . . . . . . . . . . . . . . . . . 170
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 174
7 Antibiotics That Affect the Membrane and Other Structural
Targets . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 179
7.1 Background Biochemistry Information . . . . . . . . . . . . . . . . . . . 179
7.1.1 Function of Biological Membranes . . . . . . . . . . . . . . 179
7.1.2 Composition of the Membrane . . . . . . . . . . . . . . . . . 180
7.2 Inhibition of Bacterial Membrane Function . . . . . . . . . . . . . . . . 183
7.2.1 Antiseptics and Disinfectants That Disrupt
Microbial Cell Membrane . . . . . . . . . . . . . . . . . . . . . 183
7.2.2 Antibiotics that Function by Disrupting
Microbial Cell Membrane . . . . . . . . . . . . . . . . . . . . . 186
7.3 Antibiotics Affecting Other Structural Targets . . . . . . . . . . . . . . 198
7.3.1 Triclosan, The Antibiotic That Inhibits Fatty
Acid Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 198
7.3.2 Isoniazid: Antibiotic Against Tuberculosis . . . . . . . . . 199
7.3.3 Antibiotics Targeting FtsZ, The Cell Division
Protein . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 200
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 200

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