Antibiotics: Actions, Origins, Resistance

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Christopher Walsh, ASM Press, Washington, 2003, x + 335 pp., price $99.95, ISBN: 1-55581-254-6It is just over 70 years since Gerhard Domagk discovered the sulfonamides that became the first commercially successful class of antibacterial agents. Since the mid-1930s we have experienced two distinct phases of the antibiotic revolution: the first 30 years or so, when new antibiotics were discovered or prepared almost continuously, and the bacteria seemed under control; and the period since 1965 during which only one new class of antibacterials – the oxazolidinones – has been introduced into clinical practice, and bacterial resistance has become a serious problem. At the start of the 21^st century we are left tinkering with existing structures and desperately seeking chinks in the armour of an ever more ‘cunning foe’.

To describe the bacteria as ‘cunning’ is to ascribe to them human traits they cannot possess. What they do possess is genes that have been mutating for the past 3.5 billion years, and code for the production of enzymes catalysing the production of antibacterial natural products or enzymes that destroy such products. Certain bacteria have probably always produced β-lactamases, while others have always possessed efflux pumps. What has changed during the past 70 years is that due to the evolutionary pressure to deal with the large-scale use of man-made antibacterials, the bacteria have become ever more adept at sharing the genes required for antibiotic resistance, so that most species of bacteria now have the means to reduce the efficacy of these drugs.

Christopher Walsh is well qualified to write about antibiotics, having devoted much of research career to delineating the mechanisms of antibacterial activity at the enzymatic level. He takes as his premise that an understanding of the modes of action of known antibiotics and of the bacterial resistance strategies, coupled with a greater understanding of the genetics and enzymology of the various biosynthetic pathways, should allow the eventual design of new antibacterial agents. This provides a logical framework for the book and he deals in turn with validated targets for the major antibacterial classes, resistance mechanisms, antibiotic biosynthesis, and the evolution of new strategies.

The first two sections of the book are devoted to a description of the known targets of antibiotic action: disruption of cell wall assembly, blockade of the 30S and 50S ribosomal sub-units, and inhibition of DNA gyrases and folate biosynthesis; and he concentrates on the chemistry of individual enzyme-mediated reactions. For example, his discussion of the steps controlled by the mur A to G genes for the production of peptidoglycan is both fascinating and comprehensive. His description of ribosome structure and the mechanisms by which various antibiotics disrupt ribosome-directed peptide synthesis is also rigorous and superbly illustrated – in fact the illustrations and structures throughout this book are excellent.

Section three covers the four main mechanisms of antibiotic resistance including the less well-studied one of bacterial self-defence, whereby a bacterium will, for example, glycosylate its newly produced antibacterial natural products, rendering them inactive prior to release from the cell. Enzymatic destruction of antibiotics is probably the most well-studied mechanism of inactivation, and Walsh compares the mechanism of reaction of β-lactamases and their inhibitors like clavulanic acid, thienamycin and sulbactam in great detail. The importance of efflux pumps is also emphasised, and he highlights the remarkable ability of Pseudomonas aeruginosa to avoid destruction by using a host of such pumps and an ability to change its cell membrane structure thus restricting uptake of antibiotic. Finally, he deals comprehensively with the replacement or modification of the antibiotic target. This mechanism is implicated in resistance to β-lactams (modification of penicillin-binding proteins) and vancomycin, where resistant organisms produce D-ala-D-lactate rather than D-ala-D-ala, with a concomitant loss of one H-bonding interaction and a drop of affinity for penicillin-binding protein of 1000-fold.

Walsh then moves on to antibiotic biosynthesis, and the sections on the genetics of the polyketide synthases and non-ribosomal peptide assembly will be the most familiar to readers of Natural Product Reports. He points out that the Actinomycetales – mainly represented by the Streptomyces family – produce around 8400 of the known antibiotic natural products, and that gram-positive organisms typically contain twice the number of genes found in gram-negative organisms – hence the greater wealth of natural products found in the former class. Control of the production of these antibiotics is most often effected by so-called quorum-sensing molecules like the butaneolides, and he gives a fascinating account of complexities of these and various other effectors of gene transcription. He discusses in detail the chemistry of production of ACV, vancomycin, tyrocidine, and bacitracin, together with the post-assembly chemistry needed to convert ACV into penicillins and cephalosporins, and to complete the biosyntheses of vancomycin, teicoplanin, the pristamycins, rifamicins, and bleomycins. The final chapter in this section deals with antibiotics which do not have a polyketide or non-ribosomal peptide assembly; these include fosfomycin, the aminoglycosides, chloramphenicol, and the lantibiotics. All of this material has been covered before in the pages of Natural Product Reports, but it has never before been so expertly and succinctly brought together in one publication.

The final section explores three key contemporary questions: where do we find the new antibiotics; can we accelerate the rate of discovery; and can we reduce the rate of emergence of multidrug resistance. The answer to the first question lies in bioinformatics, and Walsh points out that the newly resolved bacterial genomes have revealed a plethora of novel target genes essential for survival of the organisms. These include genes for staphylococcal sortase, transglycosylases, peptide deformylase, methionine aminopeptidase, bacterial fatty acid biosynthesis, and for quorum sensor biosynthesis. Staphylococcus aureus alone has 150 genes essential for viability. Once the gene and its enzyme product(s) have been identified, the latter can be used as targets for lead compound discovery through high-throughput screening of compound libraries. He shows how the rate of discovery of these new products will be facilitated if the synthetic libraries can be complemented by libraries of natural products produced by combinatorial biosynthesis in polyketide and non-ribosomal peptide pathways, or libraries of polyketide-non-ribosomal peptide hybrids.

Walsh has no answer to the final question on multi-drug resistance and simply recommends optimal use of these new antibiotics, and this is the only depressing part of an otherwise upbeat book. We are at a defining moment in antibacterial discovery and development, and this is the definitive book for that moment since it so lucidly and comprehensively describes the past successes and the future challenges and prospects. It is without doubt the best available book on the subject of antibiotics.

John Mann
Department of Chemistry, Queen’s University, Belfast, UK BT9 5AG

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