Biochemistry and molecular biology of antimicrobial drug action

Preface ix Preface to the sixth edition x 1 THE DEVELOPMENT OF ANTIMICROBIAL AGENTS, PAST, PRESENT AND FUTURE 1 1.1 The social and economic importance of antimicrobial agents 1 1.2 All outhne 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 iO 1.5 Current trends in the discovery of antimicrobial drugs 14 1.6 .Scope and layout of the book 15 2 VULNERABLE SHIELDS—THE CELL WALLS OF BACTERIA AND FUNGI 17 2.1 Functions of the ceU wall 17 2.2 .Structure of the bacterial wall 17 2.3 Structure and biosynthesis of peptidoglycan 22 2.4 Antibiotics that inhibit peptidoglycan biosynthesis 29 2.5 Drugs that interfere with the biosynthesis of the cell wall of mycobacteria 39 2.6 The fungal cell wall as a target for antifungal drugs 41 3 ANTIMICROBIAL AGENTS AND CELL MEMBRANES 47 3.1 Microbe killers: antiseptics and disinfectants 47 3.2 Cationic peptide antibiotics 52 3.3 lonophoric antibiotics 54 3.4 Antifungal agents that interfere with the function and biosynthesis of membrane sterols 59 4 INHIBITORS OF NUCLEIC ACID BIOSYNTHESIS 65 4.1 Compounds affecting the biosynthesis and utilization of nucleotide precursors 66 4.2 Nucleoside analogues 70 4.3 Inhibitors of the reverse transcriptase of the human immunodeficiency virus 72 4.4 Antibacterial inhibitors of topoisomerases 75 4.5 Inhibitors of DNA-dependent RNA polymerase 79 4.6 Inhibition of nucleic acid synthesis by interaction with DNA 80 5 INHIBITORS OF PROTEIN BIOSYNTHESIS 85 5.1 Ribosomes 85 5.2 Stages in protein biosynthesis 87 5.3 Puromycin 90 Contents 5.4 Inhibitors of aminoacyl-tRNA formation 91 5.5 Intiibitors of initiation and translation 92 5.6 Inhibitors of peptide bond formation and translocation 98 6 ANTIMICROBIAL DRUGS WITH OTHER MODES OF ACTION 107 6.1 Nitroheterocyclic antimicrobial agents 107 6.2 A unique antifungal antibiotic—griseofulvin 108 6.3 Antiviral agents 109 6.4 Antiprotozoal agents 113 7 ATTACK AND DEFENSE: DRUG TRANSPORT ACROSS CELL WALLS AND MEMBRANES 121 7.1 Cellular permeability barriers to drag penetration 121 7.2 Multidrug efflux 126 7.3 Facilitated uptake of antimicrobial drugs 129 8 THE GENETIC BASIS OF RESISTANCE TO ANTIMICROBIAL DRUGS 135 8.1 Mutations and the origins of drug-resistance genes 136 8.2 Gene mobility and transfer in bacterial drug resistance 140 8.3 Global regulators of drug resistance in Gram-negative bacteria 147 8.4 Genetic basis of resistance to antifungal drugs 147 9 BIOCHEMICAL MECHANISMS OF RESISTANCE TO ANTIMICROBIAL DRUGS 149 9.1 Enzymic inactivation of drugs 149 9.2 Loss or downregulation of drag activation 161 9.3 Modification of drug targets 162 9.4 Drug efflux pumps 167 9.5 Other mechanisms of resistance 170 9.6 Drug resistance and the future of antimicrobial chemotherapy 172 Index 175