Antibiotics: Challenges, Mechanisms, Opportunities (ASM Books)

__A chemocentric view of the molecular structures of antibiotics, their origins, actions, and major categories of resistance__ __Antibiotics: Challenges, Mechanisms, Opportunities__ focuses on antibiotics as small organic molecules, from both natural and synthetic sources. Understanding the chemical scaffold and functional group structures of the major classes of clinically useful antibiotics is critical to understanding how antibiotics interact selectively with bacterial targets. This textbook details how classes of antibiotics interact with five known robust bacterial targets: cell wall assembly and maintenance, membrane integrity, protein synthesis, DNA and RNA information transfer, and the folate pathway to deoxythymidylate. It also addresses the universe of bacterial resistance, from the concept of the resistome to the three major mechanisms of resistance: antibiotic destruction, antibiotic active efflux, and alteration of antibiotic targets. __Antibiotics__ also covers the biosynthetic machinery for the major classes of natural product antibiotics. Authors Christopher Walsh and Timothy Wencewicz provide compelling answers to these questions: * What are antibiotics? * Where do antibiotics come from? * How do antibiotics work? * Why do antibiotics stop working? * How should our limited inventory of effective antibiotics be addressed? __Antibiotics__ is a textbook for graduate courses in chemical biology, pharmacology, medicinal chemistry, and microbiology and biochemistry courses. It is also a valuable reference for microbiologists, biological and natural product chemists, pharmacologists, and research and development scientists. Contents 8 Preface 10 Section I: Challenges for Antibiotics 12 1 Antibiotics: Initial Concepts and Considerations 16 Waves of Resistant Bacterial Infections 17 Differential Susceptibility to Antibiotics 18 Empiric Therapy and Broad-spectrum Antibiotics 20 Antibiotic Flow Chart 21 Recent Approvals and the Current Antibiotic Pipeline 22 Recognition of Pressing Need for New Antibiotics: “The End is Near” Scenarios 23 Approach and Organization of This Volume 25 2 Major Classes of Antibiotics and Their Modes of Action 28 Antibiotics Versus Antimicrobials: Antibacterial Versus Antifungal Versus Antiprotozoal Agents 28 What Bacteria to Target 28 How to Test for Antibiotic Activity 31 How to Find Antibiotics 33 A Golden Age of Antibiotic Medicinal Chemistry 38 What is the Capacity for Microbes to Make Antibiotics? 39 Target Classes Identified from the Major Antibiotic Groups 40 A Common Pathway for Bactericidal Antibiotics? 42 Section II: Mechanisms: Antibiotic Action by Bacterial Target Class 44 3 Assembly of the Peptidoglycan Layer of Bacterial Cell Walls 48 Introduction 48 Nature of the PG Layer of the Cell Envelope 49 Biosynthesis and Insertion of PG Monomer Units 58 PG Assembly: Phase 1 in the Cytoplasm—Generation of UDP-Muramyl Pentapeptide 59 PG Assembly: Phase 2 at the Inner Face of the Cytoplasmic Membrane—the C55 Bactoprenol Lipid Carrier 64 PG Assembly: Phase III—Chain Extension and Cross-Linking at the Outer Face of the Cytoplasmic Membrane 74 Summary 78 4 Antibiotics That Block Peptidoglycan Assembly and Integrity 80 Introduction 80 PG Transpeptidase Inhibition: β-Lactam Antibiotics 80 Four Subclasses of Antibiotics: Penams, Cephems, Carbapenems, and Monobactams 82 Mechanisms of Action of Lactam Antibiotics: Acylation of Transpeptidases 83 The Families of PBPs 85 Acyl Enzyme Lifetimes Are Crucial 86 PBP Inventories 87 Many Side Chain Variants in Semisynthetic β-Lactam Antibiotics 89 The Future for β-Lactam Antibiotics? 93 Moenomycin: Inhibition of PG Transglycosylases 94 Antibiotics That Act as Substrate Binders and Sequestrants in the Bactoprenol Metabolic Cycle 96 MraY and Peptidyl Nucleoside Antibiotics 109 How Do Bacteria Respond to Categories of Antibiotics That Target the Cell Wall? 110 5 Antibiotics That Disrupt Membrane Integrity 114 Introduction 114 Antimicrobial Peptides and Defensins 114 Lantibiotic Peptides 118 Calprotectin, an Antimicrobial Protein That Complexes Mn(II) and Fe(II) 119 Bacterial Lipopeptides 119 Surfactin 120 Daptomycin Disrupts Bacterial Membrane Integrity 120 Polymyxin: an Old Antibiotic Revisited 122 Dual Mechanisms for SecondGeneration Lipoglycopeptide Antibiotics 123 6 Antibiotics That Block Protein Synthesis 126 Overview of Bacterial Protein Synthesis 127 Antibiotics That Target Aminoacyl-tRNA Synthetases 129 Antibiotics That Target the Bacterial Ribosome 131 EF-Tu: an Aminoacyl-tRNA Chaperone as Antibiotic Target 154 7 Antibiotics That Target DNA and RNA Information Transfer 160 Antibiotics Directed against Type II Topoisomerases 161 GyrB Natural Product Inhibitors—Lack of Clinical Success (to date) 166 RNA Polymerase Inhibitors as Antibiotics 168 Myxopyronins, Corallopyronin, and Ripostatin 171 8 Antibiotics That Block Biosynthesis of the DNA Building Block Deoxythymidylate 176 Thymidylate for DNA Biosynthesis 176 Formaldehyde and H4-Folate 177 Folate Biosynthesis in Microbes 178 Sulfonamide Antibiotics Target Dihydropteroate Synthase 182 Antibiotics That Block Dihydrofolate Reductase 184 Abyssomicin, a Natural Product Inhibitor of PABA Synthase 186 Section III: Mechanisms: Bacterial Resistance to Antibiotics 188 9 Bacterial Antibiotic Resistance: Overview 192 Intrinsic versus Acquired Resistance 192 Antibiotic Producers Have Many Strategies for Self-Resistance 193 Resistance by Target Class or Antibiotic Class 198 Is Resistance Inevitable? 201 The Resistome 201 How Does Nature Manage Resistance and the Resistome? 204 Is There a Case To Be Made for Synthetic Antibacterials in Terms of Lower Intrinsic Resistance? 204 Linezolid and Quinolone Resistance 205 Concluding Remarks 207 10 Antibiotic Resistance: Modification or Destruction of the Antibiotic 210 RESISTANCE TO β-LACTAMS 210 Resistance to Hybrid Polyketide/ Peptide Antibiotics: Distinct Strategies for Modification of Streptogramins A and B 225 A Suite of Enzymatic Modifications To Deactivate Aminoglycosides 226 11 Antibiotic Resistance via Membrane Efflux Pumps 232 Classes of Membrane Efflux Pumps 234 Tripartite Transenvelope Pumps in Gram-Negative Bacteria 236 Pump Regulation 238 Efflux Pump Inhibitors 239 12 Resistance via Target Modification 242 Structural Gene Mutations Are Common Mechanisms of Antibiotic Resistance 242 Methylation of 16S or 23S rRNA Molecules: Transfer of a C1 Fragment 244 Transfer of Aminoacyl or Aminoglycosyl Groups to Cell Wall Components for Resistance to Lipopeptides 246 Remodeling the Pentapeptide End of Lipid II for Glycopeptide Resistance 249 MRSA: Swapping a Sensitive for a Resistant PBP 254 13 Tuberculosis: A Formidable Challenge for Antibiotic Therapy 264 Challenges to Antibiotic Therapy in Tuberculosis 265 Vertical, Not Horizontal, Resistance in M. tuberculosis 271 MDRand XDR-TB 272 New Approaches for TB Antibiotics 274 Section IV: Mechanisms: Antibiotic Biosynthesis 284 14 Antibiotic Biosynthesis: Principles 288 The Known Natural Product Antibiotic Inventory 288 Genome Screening and Cryptic Gene Clusters 289 Elucidating the Regulatory Circuitry for Antibiotic Production by Streptomycetes 293 15 Biosynthesis of Peptide Antibiotics 300 AMPs, Lantibiotics, and Thiazolyl Peptide Antibiotics: Posttranslational Maturation of Nascent Ribosomal Peptides 305 NRPS Assembly Lines 309 Tailoring Enzymes for Glycosylation 320 Tailoring Enzymes for Oxidation of NRP Scaffolds 322 Biosynthesis of β-Lactam Antibiotics 324 16 Biosynthesis of Polyketide Antibiotics 332 The Fatty Acid Synthase Precedent: Building Blocks, Tethering, and Four-Electron Reductive Cycle 332 Distributed Polyketide Synthase Subunits Versus Multimodular Synthases 337 Macrolactone Assembly (14-, 16-, and 18-Membered Macrolactone Scaffolds) 339 Methylmalonyl-CoA as an Additional Building Block 339 Macrocyclizing TEs for Chain Release 341 Tetracycline Assembly—Type II PKS Machinery 341 Alternative Acyl-CoA Starter and Extender Units 343 Post-Assembly Line Tailoring Modifications 344 Mupirocin and Abyssomicin Assembly 346 Fungal Type I PKS Modules 349 Hybrid NRPS/PKS Assembly Lines 349 Pristinamycin PII Component 350 17 Biosynthesis of Oligosaccharide, Isoprenoid, and C-P Antibiotic Classes 356 Oligosaccharide Antibiotics 356 Isoprenoid Antibiotics 362 Carbocation Rearrangements to a Plethora of Scaffolds 364 Biosynthesis of Moenomycins, Prenylated Pentasaccharide Antibiotics 368 Phosphonate and Phosphinate Antibiotics 370 Section V: Opportunities 374 18 Underexploited Pathways and Targets for Antibiotics 378 What Molecular Genetics Did Not Tell Us about New Essential Targets That Are Robust for Antibiotic Action 378 Fatty Acid Biosynthesis 379 Nonclassical Isoprenoid Pathway Inhibitors 384 Lipopolysaccharide Biosynthesis 385 Bacterial Cell Division and Septum Formation 389 Riboswitches 394 Peptide Deformylase Inhibitors 395 Bacterial Proteases and Signal Peptidases 397 Blockade of Virulence Factor Production: Rendering the Pathogens Less Pathogenic 402 19 Prospects for New Molecules and New Targets 410 Chemical Evolution of Existing Natural Product Scaffolds 410 Underexamined Natural Product Scaffolds 412 Smart Screens for New Targets and New Antibiotic Combinations 413 Additional Screening Approaches 416 Bacterial ATPand GTP-Utilizing Enzymes as Higher-Priority Targets? 416 Where Will New Molecules Come From? 421 Combination Therapies 424 Biological Strategies for MRSA: Seeking Traction with Vaccines 427 Biological Strategies: Antibodies in Place of Small-Molecule Antibiotics 429 Phage Lysins as Antibacterial Agents 430 References 432 Index 466 Just Published! Antibiotics: Challenges, Mechanisms, Opportunities focuses on antibiotics as small organic molecules, from both natural and synthetic sourcFes. Understanding the chemical scaffold and functional group structures of the major classes of clinically useful antibiotics is critical to understanding how antibiotics interact selectively with bacterial targets. This textbook details how classes of antibiotics interact with five known robust bacterial targets: cell wall assembly and maintenance, membrane integrity, protein synthesis, DNA and RNA information transfer, and the folate pathway to deoxythymidylate. It addresses the universe of bacterial resistance, from the concept of the resistome to the three major mechanisms of resistance: antibiotic destruction, antibiotic active efflux, and alteration of antibiotic targets. Antibiotics also covers the biosynthetic machinery for the major classes of natural product antibiotics. Authors Christopher Walsh and Timothy Wencewicz provide compelling answers to these questions: Antibiotics is a textbook for graduate courses in chemical biology, pharmacology, medicinal chemistry, microbiology and biochemistry courses. It is also a valuable reference for microbiologists, biological and natural product chemists, pharmacologists, and research and development scientists. Hardcover, 477 pages, full-color illustrations, index.