Title Page -- Copyright -- Contents -- Preface -- List of Contributors -- Chapter 1 A Chemist's Survey of Different Antibiotic Classes -- 1.1 Introduction -- 1.2 Aminoglycosides -- 1.3 β-Lactams -- 1.4 Linear Peptides -- 1.4.1 Glycopeptides-Dalbaheptides -- 1.4.2 Lantibiotics -- 1.5 Cyclic Peptides -- 1.6 Thiazolylpeptides -- 1.7 Macrolactones -- 1.7.1 Macrolides -- 1.7.2 Difimicin -- 1.8 Ansamycins-Rifamycins -- 1.9 Tetracyclines -- 1.10 Oxazolidinones -- 1.11 Lincosamides -- 1.12 Pleuromutilins -- 1.13 Quinolones -- 1.14 Aminocoumarins -- References -- Chapter 2 Antibacterial Discovery: Problems and Possibilities -- 2.1 Introduction -- 2.2 Why Is Antibacterial Discovery Difficult? The Problems -- 2.3 Target Choice: Essentiality -- 2.4 Target Choice: Resistance -- 2.5 Cell Entry -- 2.6 Screening Strategies -- 2.6.1 Empirical Screens -- 2.6.2 Phenotypic Whole-Cell Screens -- 2.6.3 In Vitro Screens for Single-Target Inhibitors -- 2.6.4 Chemicals to Screen -- 2.6.4.1 Chemical Collections -- 2.7 Natural Products -- 2.8 Computational Chemistry, Virtual Screening, Structure- and Fragment-Based Drug Design (SBDD and FBDD) -- 2.9 Conclusions -- References -- Chapter 3 Impact of Microbial Natural Products on Antibacterial Drug Discovery -- 3.1 Introduction -- 3.2 Natural Products for Drug Discovery -- 3.3 Microbial Natural Products -- 3.4 The Challenge of Finding Novel Antibiotics from New Natural Sources -- 3.5 Workflow for Drug Discovery from Microbial Natural Products -- 3.6 Antimicrobial Activities: Targets for Screens -- 3.7 Natural Products: A Continuing Source for Inspiration -- 3.8 Genome Mining in Natural Product Discovery -- 3.9 Conclusions -- References -- Chapter 4 Antibiotics and Resistance: A Fatal Attraction.

4.1 To Be or Not to Be Resistant: Why and How Antibiotic Resistance Mechanisms Develop and Spread among Bacteria -- 4.1.1 Horizontal and Vertical Transmission of Resistance Genes -- 4.2 Bacterial Resistance to Antibiotics by Enzymatic Degradation or Modification -- 4.2.1 Antibiotic Resistance by Hydrolytic Enzymes -- 4.2.1.1 β-Lactamases -- 4.2.1.2 Macrolide Esterases -- 4.2.1.3 Epoxidases -- 4.2.1.4 Proteases -- 4.2.2 Antibiotic Transferases Prevent Target Recognition -- 4.2.2.1 Acyltransfer -- 4.2.2.2 Phosphotransferases -- 4.2.2.3 Nucleotidyltransferases -- 4.2.2.4 ADP-Ribosyltransferases -- 4.2.2.5 Glycosyltransferases -- 4.2.3 Redox Enzymes -- 4.3 Antibiotic Target Alteration: The Trick Exists and It Is in the Genetics -- 4.3.1 Low-Affinity Homologous Genes -- 4.3.1.1 Rifamycin Low-Affinity RpoB -- 4.3.1.2 Mutated Genes Conferring Resistance to Quinolone, Fluoroquinolone and Aminocoumarins -- 4.3.1.3 PBP2a: A Low-Affinity Penicillin-Binding Protein -- 4.3.1.4 Dihydropteroate Synthases Not Inhibited by Sulfonamide -- 4.3.2 Chemical Modification of Antibiotic Target -- 4.3.2.1 23S rRNA Modification -- 4.3.2.2 16S rRNA Modification -- 4.3.2.3 Reprogramming Chemical Composition of a Bacterial Cell-Wall Precursor -- 4.3.3 Ribosomal Protection and Tetracycline Resistance -- 4.3.4 Chromosomal Mutations in Genes Required for Membrane Phospholipid Metabolism: Lipopeptide Resistance -- 4.3.5 Covalent Modifications on Lipopolysaccharide Core Conferring Polymixine Resistance -- 4.4 Efflux Systems -- 4.4.1 The ATP-Binding Cassette (ABC) Superfamily -- 4.4.2 The Major Facilitator Superfamily (MSF) -- 4.4.3 The Small Multidrug-Resistance Family (SMR) -- 4.4.4 The Resistance-Nodulation-Division (RND) Superfamily -- 4.4.5 The Multidrug and Toxic Compound Extrusion (MATE) Family.

4.5 The Case Stories of Intrinsic and Acquired Resistances -- 4.5.1 β-Lactam Resistome of P. aeruginosa: Intrinsic Resistance Is Genetically Determined -- 4.5.2 Acquired Antibiotic Resistance in S. aureus -- 4.5.2.1 Acquired Resistance to β-Lactams and Glycopeptides -- 4.5.2.2 Acquired Resistance to Fluoroquinolones -- 4.6 Strategies to Overcome Resistance -- References -- Chapter 5 Fitness Costs of Antibiotic Resistance -- 5.1 Introduction -- 5.2 Methods to Estimate Fitness -- 5.2.1 Experimental Methods -- 5.2.2 Epidemiological Methods -- 5.3 Factors Affecting Fitness -- 5.3.1 Genetic Nature of the Resistant Determinant -- 5.3.2 Expression of the Antibiotic-Resistance Determinant -- 5.3.3 Microbial Cell Physiology, Metabolism, and Lifestyle -- 5.3.4 Genetic Background of the Antibiotic-Resistant Mutant -- 5.4 Mechanisms and Dynamics Causing Persistence of Chromosomal and Plasmid-Borne Resistance Determinants -- 5.4.1 Compensatory Genetic Mechanisms That Restore or Improve Fitness without Loss of Resistance -- 5.4.2 Linked Selection and Segregation Stability of Resistance Determinants -- 5.4.3 Reacquisition of Antimicrobial Resistance -- References -- Chapter 6 Inhibitors of Cell-Wall Synthesis -- 6.1 Introduction -- 6.2 MraY Inhibitors -- 6.3 Lipid II Targeting Compounds -- 6.3.1 Glycopeptides -- 6.3.2 Lantibiotics -- 6.3.3 Ramoplanin and Enduracidin -- 6.3.4 Other Compounds -- 6.4 Bactoprenol Phosphate -- 6.5 Conclusions -- Acknowledgments -- References -- Chapter 7 Inhibitors of Bacterial Cell Partitioning -- 7.1 Introduction -- 7.2 Bacterial Cell Division -- 7.2.1 Filamentous Temperature-Sensitive Z (FtsZ) -- 7.2.2 Structure and Assembly Properties of FtsZ -- 7.2.3 Z-Ring: A Dynamic Structure That Drives Bacterial Cell Division -- 7.2.4 Proteins Regulating FtsZ Assembly.

7.2.5 Proteins Involved in Septum Formation -- 7.2.6 Role of Other Cytoskeleton Proteins in Bacterial Cell Division -- 7.3 Cell Division Proteins as Therapeutic Targets -- 7.3.1 FtsZ as a Therapeutic Target -- 7.3.1.1 Identification of FtsZ-Targeting Antibacterial Agents -- 7.3.1.2 FtsZ Inhibitors -- 7.3.2 Other Cell Division Proteins as Therapeutic Targets -- 7.4 Status of FtsZ-Targeting Compounds: From Laboratory to Clinic -- 7.5 Conclusion -- Acknowledgment -- Abbreviations -- References -- Chapter 8 The Membrane as a Novel Target Site for Antibiotics to Kill Persisting Bacterial Pathogens -- 8.1 Introduction -- 8.2 The Challenge of Treating Dormant Infections -- 8.3 Discovery Strategies to Prevent or Kill Dormant Bacteria -- 8.4 Why Targeting the Membrane Could Be a Suitable Strategy -- 8.5 Target Essentiality and Selectivity -- 8.6 Multiple Modes of Actions -- 8.6.1 Bactericidal and Low Potential for Resistance Development -- 8.7 Therapeutic Use of Membrane-Damaging Agents against Biofilms -- 8.8 New Approaches to Identifying Compounds That Kill Dormant Bacteria -- 8.9 Challenges for Biofilm Control with Membrane-Active Agents -- 8.9.1 Test Methods -- 8.9.2 Spectrum of Activity -- 8.9.3 Pharmacological -- 8.9.4 Genetic Resistance -- 8.10 Potential for Membrane-Damaging Agents in TB Disease -- 8.11 Application to Treatment of Clostridium difficile Infection -- 8.12 Is Inhibition of Fatty Acid/Phospholipid Biosynthesis Also an Approach? -- 8.13 Concluding Remarks -- References -- Chapter 9 Bacterial Membrane, a Key for Controlling Drug Influx and Efflux -- 9.1 Introduction -- 9.2 The Mechanical Barrier -- 9.2.1 The Outer Membrane Barrier and Porin Involvement -- 9.2.2 Membrane Modification -- 9.2.3 Efflux Barrier -- 9.3 Circumventing the Bacterial Membrane Barrier.

9.3.1 Increasing the Influx: Antibiotic plus Permeabilizer, ``Increase In'' -- 9.3.1.1 Permeabilizers such as Polymyxins -- 9.3.1.2 Natural Compounds -- 9.3.1.3 Silver Nanoparticles -- 9.3.2 Blocking the Efflux: Antibiotic plus Efflux Blocker, ``Decrease Eef'' -- 9.3.2.1 The Chemical Response -- 9.3.2.2 Natural Products as Efflux Modulators -- 9.4 Conclusion -- Acknowledgments -- References -- Chapter 10 Interference with Bacterial Cell-to-Cell Chemical Signaling in Development of New Anti-Infectives -- 10.1 Introduction -- 10.2 Two-Component Systems (TCSs) as Potential Anti-Infective Targets -- 10.3 WalK/WalR and MtrB/MtrA: Case Studies of Essential TCSs as Drug Targets -- 10.4 Targeting Nonessential TCS -- 10.4.1 QseC/QseB -- 10.4.2 AgrC/AgrA -- 10.4.3 FsrC/FsrA -- 10.4.4 PhoQ/PhoP -- 10.4.5 HrpX/HrpY -- 10.5 Non-TCSs Targeting Biofilm Formation and Quorum Sensing in Pseudomonas spp. -- 10.6 Conclusions -- References -- Chapter 11 Recent Developments in Inhibitors of Bacterial Type IIA Topoisomerases -- 11.1 Introduction -- 11.2 DNA-Gate Inhibitors -- 11.2.1 Quinolones and Related Compounds -- 11.2.1.1 Development of the Fluoroquinolone Class and Mechanism of Action -- 11.2.1.2 Phase 2 Fluoroquinolones -- 11.2.1.3 Quinazolinediones (``Diones'') -- 11.2.1.4 Isothiazolones -- 11.2.2 ``NBTIs,'' Novel Bacterial Type II Topoisomerase Inhibitors -- 11.2.3 QPT (Quinoline Pyrimidine Trione) -- 11.2.4 Other DNA-Gate Inhibitors -- 11.2.4.1 Albicidin -- 11.2.4.2 Clerocidin -- 11.2.4.3 Nybomycin -- 11.2.4.4 Macromolecular Inhibitors That Stabilize Complexes with DNA -- 11.3 ATPase-Domain Inhibitors -- 11.3.1 Natural Products That Inhibit the ATPase Domain -- 11.3.1.1 Aminocoumarins -- 11.3.1.2 Cyclothialidines -- 11.3.1.3 Kibdelomycin and Amycolamicin.

11.3.2 Recent GyrB and Dual-Targeting GyrB/ParE ATPase Inhibitors.