Antibiotics: Actions, Origins, Resistance

Rating:
Summary: The Nuts & Bolts of Antibiotics
Review: This book was written by the eminent biochemist Christopher Walsh, whose broad research interests include the study of antibiotic action and resistance. It is extremely well written and organized, with an abundance of excellent illustrations. The approach is to give the reader an in depth but not exhausting coverage of several key topics in modern antibiotic research. Both novice and seasoned researcher will find much of value within the pages of this modest sized book. This important work is published at a period in time in which the resistance of a broad range of pathogenic bacteria to antibiotics has grown to alarming levels. At the same time, many pharmaceutical companies have recently abandoned research and development of new antibiotic agents.

Walsh starts the book with a brief chapter on fundamental antibiotic concepts. Where do antibiotics come from? How do they work? How does resistance develop? He next launches into a thorough review of the main classes of antibiotics, interweaving antibiotic chemical structures and targets of the drugs with the underlying microbial physiology processes that are targeted. He begins with the various classes of bacterial cell wall inhibitors, emphasizing the members of the large beta-lactam class, as well as glycopeptides and moenomycin. Next he delves into the multiple classes of protein synthesis inhibitors. He makes full use of the latest structural data emerging from X-ray crystallography of ribosomal subunits, to illustrate the mechanisms of drug action. He covers the macrolides, tetracyclines, and aminoglycosides, as well as the new glycylcyclines and oxazolidinones. The DNA topoisomerases are next featured as targets, and the interactions of quinolone antibiotics with DNA gyrase and topoisomerase. This chapter was a bit short and sparse in some details as compared to the preceding chapters, but does hit the main highlights. A final chapter in this section addresses other antibiotic classes such as the folate metabolism antagonists (sulfa drugs and trimethoprim), as well as peptide antibiotics.

The next section addresses the many mechanisms of antibiotic resistance. These four chapters examine different types of mechanisms employed by bacteria to evade antibiotics. Succinct coverage of the broad range of beta-lactamases and the aminoglycoside modifying (inactivating) enzymes are found in a chapter on enzymatic destruction or modification of antibiotics. This is followed by a very nice summary chapter around antibiotic efflux pumps, which again incorporates some structural biology. Unfortunately, the book was published just prior to the latest crystallographic studies of the RND class AcrB pump, which has added much to our understanding of efflux pumps. The final resistance chapter highlights target modification or replacement. The methicillin resistance story in Staphylococcus, mediated by PBP2a, is detailed, as is the resistance mediated by the mosaic PBP genes in pneumococci. Macrolide resistance by ribosomal methylation and the fascinating story of vancomycin resistance by the restructuring the terminal D-alanine dipeptide target is covered (Walsh's laboratory was a major contributor to the vancomycin story).

The next section of the book deals with the biosynthesis of antibiotics by producing organisms, primarily Streptomyces species. These chapters interweave the genetics and biochemistry of secondary metabolism. The signaling pathways used among producer organisms, as well as the gene regulation of the individual antibiotic biosynthetic genes, which are clustered on the chromosome are discussed. There is a chapter on each on polyketide antibiotic synthesis (erythromycins and tylosin) and non-ribosomal synthesis of peptide antibiotics (penicillins, bacitracin, vancomycin).

The book ends with 3 chapters on identifying new antibiotics. A survey of targets, both "old" and new is presented, and several suggestions for novel ways to interfere with bacterial function are briefly reviewed. Another chapter examines identifying new chemical entities with antibacterial properties. The initial part of the chapter emphasizes combinatorial chemistry approaches. Unfortunately, this process to date has led to only sparse results, with some inhibitors identified. As Walsh notes, the conversion of a chemical inhibitor of an antibacterial enzyme target to a lead compound that can be subsequently endowed with all the myriad pharmacological properties necessary to be a drug is an extremely daunting task. The vast majority of compounds identified cannot be successfully modified to possess the properties necessary to be a drug. A second approach that he covers, the modification by genetic means of antibiotic producing organisms to synthesize new antibiotics (combinatorial biosynthesis), may be more promising.

Walsh closes out the book with some thought provoking chapters around the proper use of antibiotics, and strategies to minimize resistance development. He highlights the antibiotic resistant pathogens of the 21st century, and the continued problem of methicillin resistant staphylococci and vancomycin resistant enterococci. He makes it abundantly clear that there has been no victory in the fight against infectious diseases, and the reports from the front lines are less than encouraging for the future.

Rating:
Summary: The Nuts & Bolts of Antibiotics
Review: This book was written by the eminent biochemist Christopher Walsh, whose broad research interests include the study of antibiotic action and resistance. It is extremely well written and organized, with an abundance of excellent illustrations. The approach is to give the reader an in depth but not exhausting coverage of several key topics in modern antibiotic research. Both novice and seasoned researcher will find much of value within the pages of this modest sized book. This important work is published at a period in time in which the resistance of a broad range of pathogenic bacteria to antibiotics has grown to alarming levels. At the same time, many pharmaceutical companies have recently abandoned research and development of new antibiotic agents.

Walsh starts the book with a brief chapter on fundamental antibiotic concepts. Where do antibiotics come from? How do they work? How does resistance develop? He next launches into a thorough review of the main classes of antibiotics, interweaving antibiotic chemical structures and targets of the drugs with the underlying microbial physiology processes that are targeted. He begins with the various classes of bacterial cell wall inhibitors, emphasizing the members of the large beta-lactam class, as well as glycopeptides and moenomycin. Next he delves into the multiple classes of protein synthesis inhibitors. He makes full use of the latest structural data emerging from X-ray crystallography of ribosomal subunits, to illustrate the mechanisms of drug action. He covers the macrolides, tetracyclines, and aminoglycosides, as well as the new glycylcyclines and oxazolidinones. The DNA topoisomerases are next featured as targets, and the interactions of quinolone antibiotics with DNA gyrase and topoisomerase. This chapter was a bit short and sparse in some details as compared to the preceding chapters, but does hit the main highlights. A final chapter in this section addresses other antibiotic classes such as the folate metabolism antagonists (sulfa drugs and trimethoprim), as well as peptide antibiotics.

The next section addresses the many mechanisms of antibiotic resistance. These four chapters examine different types of mechanisms employed by bacteria to evade antibiotics. Succinct coverage of the broad range of beta-lactamases and the aminoglycoside modifying (inactivating) enzymes are found in a chapter on enzymatic destruction or modification of antibiotics. This is followed by a very nice summary chapter around antibiotic efflux pumps, which again incorporates some structural biology. Unfortunately, the book was published just prior to the latest crystallographic studies of the RND class AcrB pump, which has added much to our understanding of efflux pumps. The final resistance chapter highlights target modification or replacement. The methicillin resistance story in Staphylococcus, mediated by PBP2a, is detailed, as is the resistance mediated by the mosaic PBP genes in pneumococci. Macrolide resistance by ribosomal methylation and the fascinating story of vancomycin resistance by the restructuring the terminal D-alanine dipeptide target is covered (Walsh's laboratory was a major contributor to the vancomycin story).

The next section of the book deals with the biosynthesis of antibiotics by producing organisms, primarily Streptomyces species. These chapters interweave the genetics and biochemistry of secondary metabolism. The signaling pathways used among producer organisms, as well as the gene regulation of the individual antibiotic biosynthetic genes, which are clustered on the chromosome are discussed. There is a chapter on each on polyketide antibiotic synthesis (erythromycins and tylosin) and non-ribosomal synthesis of peptide antibiotics (penicillins, bacitracin, vancomycin).

The book ends with 3 chapters on identifying new antibiotics. A survey of targets, both "old" and new is presented, and several suggestions for novel ways to interfere with bacterial function are briefly reviewed. Another chapter examines identifying new chemical entities with antibacterial properties. The initial part of the chapter emphasizes combinatorial chemistry approaches. Unfortunately, this process to date has led to only sparse results, with some inhibitors identified. As Walsh notes, the conversion of a chemical inhibitor of an antibacterial enzyme target to a lead compound that can be subsequently endowed with all the myriad pharmacological properties necessary to be a drug is an extremely daunting task. The vast majority of compounds identified cannot be successfully modified to possess the properties necessary to be a drug. A second approach that he covers, the modification by genetic means of antibiotic producing organisms to synthesize new antibiotics (combinatorial biosynthesis), may be more promising.

Walsh closes out the book with some thought provoking chapters around the proper use of antibiotics, and strategies to minimize resistance development. He highlights the antibiotic resistant pathogens of the 21st century, and the continued problem of methicillin resistant staphylococci and vancomycin resistant enterococci. He makes it abundantly clear that there has been no victory in the fight against infectious diseases, and the reports from the front lines are less than encouraging for the future.