Note: Cover -- Half Title -- Title -- Copyright -- Preface -- Contents -- Contributors -- 1. Global Aspects of Antibiotic Resistance -- 2. Genomics of Bacterial Pathogens -- 3. Bioinformatics, Genomics, and Antimicrobial Drug Discovery -- 4. The Pathway Tools Software and Its Role in Antimicrobial Drug Discovery -- 5. Genomic Strategies in Antibacterial Drug Discovery -- 6. Genomics-Based Approaches to Novel Antimicrobial Target Discovery -- 7. Pathogenesis Genes as Novel Targets -- 8. Application of Genomics to the Discovery of New Drugs Against Tuberculosis -- 9. Phenotype Micro Arrays: Their Use in Antibiotic Discovery -- 10. Microbial Proteomics: New Approaches for Therapeutic Vaccines and Drug Discovery -- 11. Surrogate Ligand-Based Assay Systems for Discovery of Antibacterial Agents for Genomic Targets -- 12. Expression Profiling Uses in Antibacterial Chemotherapy Development -- 13. Using Fungal Genomes for the Discovery, Development, and Clinical Application of Novel and Current Antifungal Therapeutics -- 14. Genomics in Novel Natural Products Generation -- Index.

Note: Intro -- Antibiotic Discovery and Development -- Foreword -- References -- Contents -- Contributors -- Part I: Introductory History of Antimicrobial Drugs -- Chapter 1: The Early History of Antibiotic Discovery: Empiricism Ruled -- 1.1 Introduction -- 1.2 Birth of Chemotherapy -- 1.2.1 Ehrlich's Discovery of Salvarsan -- 1.2.2 Prontosil: Forerunner of the Sulfonamides -- 1.3 Natural Products Enter the Scene -- 1.3.1 Discovery of Penicillin -- 1.3.2 The Actinomycetes Take Center Stage -- 1.3.2.1 The Discovery of Streptomycin -- 1.4 The Pharmaceutical Industry Initiates Screening: Collaboration and Competition -- 1.4.1 Isolation of Novel Producer Organisms -- 1.4.2 Screening for Activity -- 1.4.3 Isolating and Identifying the Active Metabolite -- 1.5 Antibiotics Produced by Actinomycetes -- 1.5.1 Chlortetracycline -- 1.5.2 Chloramphenicol -- 1.5.3 Additional Aminoglycoside Antibiotics -- 1.5.3.1 Neomycin -- 1.5.3.2 Kanamycin -- 1.5.3.3 Gentamycin -- 1.5.4 Erythromycin A: The Macrolide Prototype -- 1.5.5 Lincomycin -- 1.5.6 Vancomycin: The Glycopeptide Prototype -- 1.5.7 Rifamycins: The First Ansamacrolides -- 1.5.8 Novobiocin -- 1.5.9 Spectinomycin -- 1.5.10 Daptomycin : The First Lipopeptide to Be Marketed -- 1.5.11 Streptogramins: A Natural Synergy -- 1.6 Antibiotics Produced by Fungi -- 1.6.1 The Discovery of Cephalosporin C -- 1.6.2 Fusidic Acid -- 1.7 Antibiotics Produced by Bacteria that are not Actinomycetes -- 1.7.1 Bacitracin: A Gram-Positive Only Peptide Antibiotic -- 1.7.2 Polymyxins: Gram-Negative Only Peptide Antibiotics -- 1.8 Antibiotics Produced Through Synthetic Chemistry -- 1.8.1 Para Amino Salicylic Acid -- 1.8.2 Isoniazid -- 1.8.3 Pyrazinamide -- 1.8.4 Ethambutol -- 1.8.5 Nitrofurans -- 1.8.6 Metronidazole -- 1.8.7 Nalidixic Acid: The Prototype Quinolone -- 1.8.8 Linezolid: The First Oxazolidinone to Be Approved. , 1.9 Concluding Comments -- References -- Chapter 2: Rational Approaches to Antibacterial Discovery: Pre-Genomic Directed and Phenotypic Screening -- 2.1 Introduction -- 2.2 Antibacterial Chemotherapeutics: Antimetabolites Versus Enzyme Inhibitors -- 2.2.1 Prontosil -- 2.2.2 Trimethoprim -- 2.3 Natural Product Screening -- 2.3.1 Dereplication -- 2.3.2 Screening as a Means of Dereplication -- 2.4 Rational Screening for Inhibitors of Cell Wall Synthesis -- 2.4.1 b  -Lactamase Inhibitors -- 2.4.2 Screens for Spheroplast Formation -- 2.4.2.1 Mechanisms of Action of Spheroplasting Compounds Acting Outside the Committed Steps of the Cell Wall Pathway -- Fosmidomycin and Other Phosphonates -- Pentalenolactone -- Globomycin -- 2.4.3 Strains Supersensitive to Cell Wall Active Agents -- 2.4.4 Acholeplasma Screen -- 2.4.5 L-Form Assay -- 2.4.6 Specific Screens for Novel Glycopeptides Based on Mechanism of Action -- 2.4.7 Competition with Unfractionated Cell Wall Material -- 2.4.8 b  -Lactamase Inducers -- 2.4.9 Synergy Screens -- 2.5 Screens for New Members of Previously Described Classes of Antibiotics -- 2.5.1 Aminoglycoside Screens -- 2.5.2 Reporter-Based Screening Platforms -- 2.6 The Concept of Phenotypic Screening -- 2.6.1 Folate Pathway Revisited: Interplay of Genetics, Biochemistry, and Screening Strategies -- 2.6.2 Phenotypic Screening for DNA Replication Inhibitors -- 2.7 Why Rational Screening Has Had a Low Yield: Implications for Current Programs -- References -- Part II: Marketed Major Classes of Compounds -- Chapter 3: Beta-Lactam Antibiotics -- 3.1 Introduction -- 3.2 Development of Penicillins -- 3.2.1 The Natural Penicillins -- 3.2.2 The Hunt for Penicillinase-Stable Penicillins -- 3.2.3 Penicillins with Improved Oral Bioavailability -- 3.2.4 Penicillins with Improved Stability to Staphylococcal Penicillinase. , 3.2.5 Broad-Spectrum and Beta-Lactamase Stable Penicillins -- 3.2.6 Experimental Penams -- 3.3 Cephalosporins, Cephamycins and Other Cephems -- 3.3.1 First-Generation Cephalosporins -- 3.3.2 Second-Generation Cephalosporins -- 3.3.3 Third-Generation Cephalosporins -- 3.3.4 Fourth-Generation Cephalosporins -- 3.3.5 Anti-MRSA Cephalosporins -- 3.3.6 Cephamycins -- 3.3.7 Chitinovorins and Cephabacins -- 3.3.8 Carbacephems and Oxacephems -- 3.3.9 Experimental Cephems -- 3.4 Carbapenems -- 3.5 Penems and Oxapenems -- 3.6 Monocyclic Beta-Lactams -- 3.7 Antibiotic Combinations with Beta-Lactamase Inhibitors -- 3.8 Beta-Lactam Mimics -- 3.9 Pharmacology -- References -- Chapter 4: Review of the Quinolone Family -- 4.1 Introduction -- 4.2 Structure Activity Relationships -- 4.3 Mechanism of Action -- 4.4 Mechanisms of Resistance -- 4.4.1 Chromosomal Mechanisms -- 4.4.2 Plasmid-Mediated Mechanisms -- 4.5 Antimicrobial Activity -- 4.6 Pharmacokinetics -- 4.7 Pharmacodynamics -- 4.8 Toxicity -- 4.9 Clinical Uses -- 4.9.1 Urinary Tract Infections -- 4.9.2 Sexually Transmitted Diseases -- 4.9.3 Gastrointestinal and Abdominal Infections -- 4.9.4 Respiratory Tract Infections -- 4.9.5 Bone and Joint Infections -- 4.9.6 Skin and Soft-Tissue Infections -- 4.9.7 Other Infections -- References -- Chapter 5: Tetracyclines -- 5.1 Introduction -- 5.2 History of Tetracycline -- 5.2.1 The Natural Products Approach to Antibiotic Discovery -- 5.2.2 The Discovery of the First Tetracycline -- 5.2.3 Biosynthesis of the Tetracyclines -- 5.2.4 Expanding the Utility Through Semi-Synthesis -- 5.2.5 A New Generation of Tetracyclines: The Glycylcyclines and Aminomethylcyclines -- 5.3 Tigecycline -- 5.3.1 Mechanism of Action -- 5.3.2 Spectrum of Activity -- 5.3.2.1 Reference Susceptibility Test Method -- 5.3.2.2 Susceptibility Test Data -- 5.3.3 Mechanisms of Resistance to Tigecycline. , 5.3.3.1 S. aureus -- 5.3.3.2 The Proteeae and P. aeruginosa -- 5.3.3.3 Other Enterobacteriaceae -- 5.3.3.4 Acinetobacter baumannii -- 5.3.4 Clinical Indications -- 5.3.4.1 Complicated Skin and Skin Structure Infections -- 5.3.4.2 Complicated Intra-Abdominal Infections -- 5.3.4.3 Community Acquired Pneumonia -- 5.4 Concluding Remarks -- References -- Chapter 6: Macrolides and Ketolides -- 6.1 Introduction -- 6.2 Development History and Chemistry -- 6.3 In Vitro Antibacterial Activity -- 6.4 Mechanism of Action -- 6.5 Mechanism of Resistance -- 6.6 Pharmacokinetics and Pharmacodynamics -- 6.7 Clinical Use -- 6.7.1 Upper Respiratory Tract Infections -- 6.7.1.1 Bacterial Pharyngitis -- 6.7.1.2 Acute Maxillary Sinusitis -- 6.7.1.3 Acute Otitis Media -- 6.7.2 Lower-Respiratory Tract Infections -- 6.7.2.1 Acute Bacterial Exacerbations of Chronic Obstructive Pulmonary Disease -- 6.7.2.2 Acute Bacterial Exacerbation of Chronic Bronchitis (ABECB) -- 6.7.2.3 Community-Acquired Bacterial Pneumonia (CABP) -- 6.7.3 Skin and Soft Tissue Infections -- 6.7.4 Genital Infections -- 6.7.5 Mycobacterial Infections in AIDS Patients -- 6.7.6 Other Pathogens -- 6.7.7 Other Proposed Antibacterial Uses of Macrolides -- 6.7.7.1 Atherosclerosis -- 6.7.7.2 Asthma -- 6.7.7.3 Crohn's Disease -- 6.7.8 Proposed Anti-inflammatory Uses of Macrolides -- 6.7.8.1 Diffuse Panbronchiolitis/Cystic Fibrosis -- 6.7.8.2 Other Inflammatory Conditions -- 6.8 Safety Issues -- 6.8.1 Erythromycin -- 6.8.2 Clarithromycin -- 6.8.3 Azithromycin -- 6.8.4 Telithromycin -- 6.8.5 Drug-Drug Interactions -- 6.9 Future Directions -- References -- Chapter 7: Aminoglycosides -- 7.1 Introduction -- 7.2 Aminoglycoside Mechanism of Action -- 7.3 Mechanisms of Aminoglycoside Resistance -- 7.4 Aminoglycoside Natural Products -- 7.5 History, the Semisynthetic Era. , 7.6 The "Neoglycoside" ACHN-490 is Active Against Bacteria with AMEs -- 7.6.1 ACHN-490 is Active Against Bacteria Resistant to Key Antibiotics -- 7.6.2 ACHN-490 is Rapidly Bactericidal -- 7.6.3 ACHN-490 is Synergistic with Other Agents Against MRSA -- 7.7 Aminoglycoside Pharmacokinetics -- 7.7.1 Pharmacokinetics of ACHN-490 -- 7.8 Aminoglycoside Pharmacodynamics -- 7.9 Toxicity and Safety of Aminoglycosides -- 7.9.1 Aminoglycoside-Associated Neuromuscular Blockade -- 7.9.2 Nephrotoxicity -- 7.9.3 Renal Uptake of Aminoglycosides -- 7.9.4 Mechanisms of Cellular Toxicity -- 7.9.5 Aminoglycoside Ototoxicity -- 7.9.6 Ototoxicity in Humans -- 7.9.7 Uptake into Inner Ear Cells -- 7.10 Conclusion -- References -- Chapter 8: Oxazolidinone Antibacterial Agents -- 8.1 Introduction -- 8.2 Discovery of the Oxazolidinones -- 8.2.1 Emergence of Antibacterial Oxazolidinones at DuPont -- 8.3 The First Clinically Useful Oxazolidinone, Linezolid -- 8.3.1 Identification of Oxazolidinones with Improved Safety Profiles at the Upjohn Company -- 8.3.2 Upjohn Studies Leading to the Identification of PNU-100480, Eperezolid and Linezolid -- 8.3.3 Linezolid Emerges as the Oxazolidinone with the Best Overall Profile -- 8.3.4 Clinical Experience with Linezolid -- 8.3.5 Linezolid Indications (Marketed as Zyvox™) -- 8.4 Other Noteworthy Oxazolidinones -- 8.4.1 Additional Key Contributions to Oxazolidinone SAR -- 8.4.1.1 Oxazolidinone Ring Replacements -- 8.4.1.2 Evolution of the Oxazolidinone C-5 Side Chain -- 8.4.1.3 Oxazolidinones with Extended Binding Motifs -- 8.4.2 Post-linezolid Clinical Oxazolidinones -- 8.4.2.1 Oxazolidinones Under Active Clinical Investigation -- 8.5 Oxazolidinone Mechanism of Action and Resistance Development -- 8.5.1 Mechanism of Action -- 8.5.2 Resistance Development -- 8.5.2.1 Staphylococci -- 8.5.2.2 Enterococci -- 8.5.2.3 Streptococci. , 8.6 Oxazolidinone Opportunities and Conclusions.