Biochemistry and Molecular Biology of Antimicrobial Drug Action
Biochemistry and Molecular Biology of Antimicrobial Drug Action Fifth edition Formerly Biochemistry of Antimicrobial Action T. J. Franklin and G. A. Snow Zeneca Pharmaceuticals Alderley Park, Macclesfield Cheshire KLUWER ACADEMIC PUBLISHERS DORDRECHT/BOSTON/LONDON
Library of Congress Cataloging in Publication Card Number: 98-70539 ISBN 978-0-412-82190-5 ISBN 978-94-010-9127-5 (ebook) DOl 10.1007/978-94-010-9127-5 Published by Kluwer Academic Publishers, P.O. Box 17, 3300 AA Dordrecht, The Netherlands. Sold and distributed in North, Central and South America by Kluwer Academic Publishers, 101 Philip Drive, Norwell, MA 02061, U.S.A.. In all other countries, sold and distributed by Kluwer Academic Publishers Group, P.O. Box 322, 3300 AH Dordrecht, The Netherlands. All Rights Reserved 1998 The Kluwer Academic Publishers Softcover reprint of the hardcover 1st edition 1998 No part of the material protected by this copyright notice may be reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, or by any information storage and retrieval system, without prior permission from the copyright owner.
This edition is dedicated to the memory of Dr G. Alan Snow, 1915-1995, my co-author, colleague and mentor.
The cover illustration shows a computer-generated graphic of Penicillin V ' ~ p h e n o xpenicillin) y m e t hkindly y l provided by Mr A.M. Slater
Contents Preface Preface to the fifth edition IX Xl 1 THE DEVELOPMENT OF ANTIMICROBIAL AGENTS PAST, PRESENT AND FUTURE 1 1.1 The social and economic importance of antimicrobial agents 1 1.2 An outline of the historical development of antimicrobial agents 2 1.3 Reasons for studying the biochemistry and molecular biology of antimicrobial compounds 9 1.4 Uncovering the molecular basis of antimicrobial action 10 1.5 Scope and layout of the present book 13 2 VULNERABLE SHIELDS - THE CELL WALLS OF BACTERIA AND FUNGI 15 2.1 Functions of the cell wall 15 2.2 Structure of the bacterial wall 15 2.3 Structure and biosynthesis of peptidoglycan 19 2.4 Antibiotics that inhibit peptidoglycan biosynthesis 26 2.5 Drugs that interfere with the biosynthesis of the cell wall of mycobacteria 37 2.6 The structure of the fungal cell wall 2.7 Inhibitors of the biosynthesis of the fungal cell wall 38 39 3 ANTISEPTICS, ANTIBIOTICS AND THE CELL MEMBRANE 43 3.1 Microbe killers: antiseptics and disinfectants 43 3.2 Polypeptide antibiotics 46 3.3 Ionophoric antibiotics 49 3.4 Antifungal agents that interfere with the function and biosynthesis of membrane sterols 55 4 INHIBITORS OF NUCLEIC ACID SYNTHESIS 61 4.1 Compounds affecting the biosynthesis and utilization of nucleotide precursors 62 4.2 Inhibitors of nucleic acid biosynthesis at the polymerization stage 66 5 INHIBITORS OF PROTEIN BIOSYNTHESIS 77 5.1 Ribosomes 77 5.2 Stages in protein biosynthesis 78 5.3 Puromycin 81 5.4 Inhibitors of aminoacyl-trna formation 82 5.5 Inhibitors of initiation and translation 83 5.6 Inhibitors of peptide bond formation and translocation 89 vii
Contents 5.7 Nitrofurantoin - a ribosomal poison? 5.8 Effects of inhibitors of 70S ribosomes on eukaryotic cells 6 ANTIMICROBIAL DRUGS WITH OTHER MODES OF ACTION 6.1 Antibacterial agents 6.2 A unique antifungal antibiotic - griseofulvin 6.3 Antiviral agents 6.4 Antiprotozoal agents 7 PENETRATING THE DEFENCES: HOW ANTIMICROBIAL DRUGS REACH THEIR TARGETS 7.1 Cellular permeability barriers to drug penetration 7.2 Multidrug efflux in bacteria 7.3 Examples of the uptake of antibacterial drugs 7.4 Uptake of antimicrobial drugs by eukaryotic pathogens 95 95 97 97 98 98 101 107 107 111 113 117 8 THE GENETIC BASIS OF RESISTANCE TO ANTIMICROBIAL DRUGS 119 8.1 Mutations and the origins of drug-resistance genes 120 8.2 Gene mobility and transfer in bacterial drug resistance 123 8.3 Global regulators of drug resistance in Gram-negative bacteria 131 9 BIOCHEMICAL MECHANISMS OF RESISTANCE TO ANTIMICROBIAL DRUGS 133 9.1 Enzymic inactivation of drugs 133 9.2 Modification of drug targets 145 9.3 Drug efflux pumps 151 9.4 Other mechanisms of resistance 154 9.5 Drug resistance and the future of chemotherapy 155 Index 159 viii
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 of key articles and books for further reading at the end of each chapter. We have drawn on the work of many scientists and we are especially pleased to express our thanks to those who have given us permission to reproduce their original diagrams and photographs. We are also grateful to the Pharmaceuticals Division of Imperial Chemicals Industries Ltd, for providing the necessary facilities for the preparation of this book. Abbreviations used without definition for common biochemical substances are those recommended by the Biochemical Journal (1970). June 1970 T. J. FRANKLIN G. A. SNOW ix
Preface to the fifth edition Since the previous edition of this book there have been major developments in medicine and its underpinning basic sciences. The problems posed by infectious diseases afflicting humans and their domestic animals have attracted increasing publicity and concern throughout this period. The menace of AIDS continues unabated and has reached epidemic proportions in parts of the developing world. The spread of multidrug-resistant bacteria is seemingly unstoppable, sporadic outbreaks of meningitis, bacterially mediated food poisoning and lethal viral infections out of Africa regularly alarm the public. Fortunately, against this somewhat gloomy picture can be set some notable advances. The impact of rapidly advancing technologies in molecular biology (that have prompted the expansion of the title of this book) on our understanding of the mechanisms of antimicrobial action and drug resistance has been remarkable. Valuable new antimicrobial drugs have emerged in all areas of infectious disease, perhaps most notably in the treatment of AIDS, where combinations of several new anti-hiv compounds have brought new hope to victims of this appalling disease. In this new edition attention concentrates largely on the action of compounds in clinical use against micro-organisms; earlier accounts of anticancer compounds have been omitted since these now form a large subject in its own right. Rapidly expanding knowledge of the molecular genetics and biochemistry of antimicrobial drug resistance has required separate chapters on each of these topics. A separate chapter has also been devoted to drugs with biochemical activities that could not be included within the main mechanisms described in Chapters 2,3,4 and 5. Drs Bob Nolan and Keith Barret-Bee, who were major contributors to the fourth edition, have since moved on to new fields of endeavour and, sadly, Alan Snow died in 1995. Although I must therefore take sole responsibility for the content of this new edition, I have been greatly helped by the incisive comments of my colleagues Drs Terry Hennessey and Wright Nichols on certain sections of the book. Over the years many helpful comments and criticisms from our readers have been invaluable in planning future editions. I hope that they will continue to let me have their views. Finally I would like to express my thanks to Zeneca Pharmaceuticals for the provision of facilities which have made this new edition possible. TREVOR J. FRANKLIN