Biochemistry of Antimicrobial Action

235 Pages·1975·9.49 MB·English

by  T. J. Franklin

Biochemistry of Antimicrobial Action
Biochemistry of
Antimicrobial Action
Second Edition
T. 1. F RAN K LIN and G. A. S NOW
Imperial Chemical Industries Ltd.,
Pharmaceuticals Division, Alderley Park,
Macclesfield, Cheshire
SPRINGER-SCIENCE+BUSINESS MEDIA, B.V.
First published 1971
by Chapman and Hall Ltd.,
11 New Fetter Lane, London EC 4EE
Second edition 1975
© 1975 T. J. Franklin and G. A. Snow
Originally published by Chapman & Hall in 1975
Typeset by Preface Ltd.,
Salisbury, Wiltshire
ISBN 978-0-412-12910-0 ISBN 978-1-4899-3412-3 (eBook)
DOI 10.1007//978-1-4899-3412-3
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Ubrary of Congress Catalog Card Number 75-8549
Contents
Page
Preface xi
Preface to the second edition xiii
1 The Development of Antimicrobial Agents, Past, Present,
and Future
The social and economic importance of antimicrobial
q~b 1
An outline of the historical development of
antimicrobial agents and of chemotherapeutic theories 2
Early remedies 2
Antiseptics and disinfectants 3
The beginnings of chemotherapy 4
The debt of chemotherapy to Ehrlich 7
The treatment of bacterial infeotions by synthetic
compounds 10
The antibiotic revolution 11
Reasons for studying the biochemistry of antimicrobial
compounds 13
Development of biochemical knowledge of
antimicrobial action 14
Pharmacological biochemistry 14
Nature of the biochemical systems affected 15
Methods used for the study of the mode of action of
antimicrobial compounds 15
Selectivity of action of antimicrobial agents 18
The molecular interaction between the antimicrobial
agent and the target site 19
The biochemistry of microbial resistance 19
Scope and layout of the present book 20
v
vi Contents
2 The Bacterial Cell Wall- A Vulnerable Shield 22
Functions of the wall 22
Wall structure 23
The Gram-positive wall 23
The Gram-negative wall 26
Structure and biosynthesis of murein 29
Stage 1. Synthesis of uridinediphospho-N-
acetylmuramic acid 30
Stage 2. Building the pentapeptide side chain 32
Stage 3. Membrane-bound reactions leading to a
linear Polysaccharide polymer 33
Stage 4. Cross-linking 35
Other mureins 38
Antibiotics having a primary action on murein
biosynthesis 39
Phosphonomycin 40
Cycloserine (Oxamycin) 40
Vancomycin, enduracidin and moenomycin 42
Penicillins and cephalosporins 43
Bacitracin 52
Fungal walls 53
3 Antiseptics, Antibiotics and the Cell Membrane 56
Bacteria killers: antiseptics and disinfectants 56
Pheno~ 59
Cationic antiseptics 60
Polypeptide antibiotics 62
The polyene antibiotics 66
Ionophoric antibiotics 68
Gramicidin A 72
4 Suppression of Gene Function 1. Inhibitors of the
Synthesis of Nucleic Acids 76
Types of inhibitors of nucleic acid synthesis 77
Inhibitors of the biosynthesis of nucleotide precursors 77
Azaserine and 6-diazo-5-oxO-L -norleucine (DON) 77
Hadacidin 80
Psicofuranine and decoyinine 81
Mycophenolic acid 82
Inhibitors of nucleic acid synthesis at the polymerization
level 84
Contents vii
The intercalating dyes: acridines, phenanthridines and
chloroquine 84
Actinomycin D 90
Cross-linking of DNA: mitomycin and porfiromycin 97
Rifamycins, streptovaricins and streptolydigin:
inhibitors of RNA polymerase 100
Hydroxyphenylazopyrimidines: inhibitors of DNA
polymerase 103
Nalidixic acid 106
5-Iododeoxyuridine 107
5 Suppression of Gene Function 2. Interference with the
Translation of the Genetic Message: Inhibitors of Protein
Synthesis 109
Stages in protein biosynthesis 110
Initiation 110
Peptide bond synthesis and chain elongation 112
Chain termination and release 113
Puromycin 114
Inhibition of initiation complex formation and transfer
RNA-ribosome interaction 116
Streptomycin 116
Other aminoglycoside antibiotics 121
Tetracyclines 123
Inhibitors of peptide bond formation and translocation 126
Chloramphenicol 126
Erythromycin 128
Lincomycin and clindamycin 129
Fusidic acid 130
Cycloheximide 131
Some consequences of interference with protein
synthesis 132
Effects in prokaryotic cells 132
Effects in eukaryotic cells 136
6 Synthetic Antimicrobial Agents and Compounds with
Special Applications 139
The sulphonamide antibacterials 139
Antagonists of dihydrofolate reductase 144
Antimicrobial agents affecting terminal respiration 147
Antimycin 147
viii Contents
Oligomycin 149
The sideromycins 151
Other antibacterial and antifungal agents 152
Novobiocin 152
Quinoxaline and phenazine N-oxides 153
The nitrofuran antibacterials 153
Isonicotinic hydrazide 1S 4
Griseofulvin 154
Compounds used in treating protozoal diseases 154
Chemotherapy of virus diseases 157
7 Penetrating the Defences: How Antimicrobial Agents
Reach Their Targets 160
Cellular permeability barriers to drug penetration 161
The cy toplasmic membrane 161
The outer layers of bacterial cells 163
Some examples of modes of penetration of specific
antibacterial agents 167
Passive diffusion 167
Facilitated diffusion 169
The exploitation of cellular transport systems in the
design of new chemotherapeutic agents 172
8 The Problems of Resistance to Antimicrobial Drugs 175
The genetics of drug-resistance 176
The nature of genotypic alterations giving rise to
drug-resistant variants 177
Spontaneous mutations 177
Spread of drug-resistance by the transfer of genetic
information 177
Transformation 177
Transduction 179
Conjugation and R-factors 180
Biochemical mechanisms of drug-resistance 188
Summary of possible mechanisms 188
( 1) Conversion of an active drug to an inactive
derivative 189
(2) Modification of drug-sensitive site 198
(3) Loss of cell permeability to a drug 200
(4) Increased production of a drug-sensitive enzyme 204
Contents ix
(5) Increased production of a metabolite that
antagonizes the inhibitor 204
(6) Enhancement of an alternative metabolic route
bypassing the inhibited pathway 205
(7) Decreasedrequirement for a product of an
inhibited reaction 206
Practical approaches to the con trol of drug-resistance 206
Index 209
Preface
The rapid advances made in the study of the synthesis, structure and
function of biological macromolecules in the last fifteen years have
enabled scientists concerned with antimicrobial agents to achieve a
considerable measure of understanding of how these substances
inhibit cell growth and division. The use of antimicrobial agents as
highly specific inhibitors has in turn substantially assisted the
investigation of complex biochemical processes. The literature in this
field is so extensive however, that we considered an attempt should
be made to draw together in an introductory book the more
significant studies of recent years. This book, which is in fact based
on lecture courses given by us to undergraduates at Liverpool and
Manchester Universities, is therefore intended as an introduction to
the biochemistry of antimicrobial action for advanced students in
many disciplines. We hope that it may also be useful to established
scientists who are new to this area of research.
The book is concerned with a discussion of medically important
antimicrobial compounds and also a number of agents that, although
having no medical uses, have proved invaluable as research tools in
biochemistry. Our aim has been to present the available information
in a simple and readable way, emphasizing the established facts
rather than more controversial material. Whenever possible, however,
we have indicated the gaps in the present knowledge of the subject
where further information is required. We have avoided the use of
literature references in the text; instead we have included short lists
xi