Inhalt

1 History of ?-Lactam Antibiotics.- A. The Past Fifty Years.- I. Fleming's Discovery.- II. Discovery of the Therapeutic Power of Penicillin in Systemic Infections.- III. Large-Scale Production.- IV. Wartime Interest in Penicillin in Europe and Japan.- V. Isolation, Structure, and Synthesis.- VI. Penicillin-Resistant Bacteria.- VII. 6-Aminopenicillanic Acid and New Penicillins.- VIII. 7-Aminocephalosporanic Acid and the Cephalosporins.- IX. New ?-Lactam Compounds.- X. Biosynthesis.- XI. Mode of Action and Resistance.- B. The Future.- References.- 2 Mode of Action of ?-Lactam Antibiotics - A Microbiologist's View.- A. Introduction.- I. Mode of Action Studies: Benefits for Basic and Applied Sciences.- II. Mode of Action of Penicillin: A Multilevel Problem.- B. Journey of the Extracellular Antibiotic to the Intracellular Targets.- I. Extracellular Barriers.- II. Barriers in the Bacterial Envelope.- III. The Outer Membrane of Gram-Negative Bacteria.- IV. The End of the Journey: Arrival at the Plasma Membrane.- C. The Biochemical Targets of ?-Lactam Antibiotics.- I. Selective Toxicity of ?-Lactams.- II. Localization of Radioactively Labeled Penicillin in Bacteria.- III. Morphological and Biochemical Effects of Penicillin.- IV. Penicillin-Sensitive Enzymes.- 1. Molecular Basis of Specificity.- 2. Studies with Model Substrates and Model Enzymes.- V. Penicillin-Binding Proteins (PBPs).- 1. Enzymatic Activity of PBPs with Model Substrates.- 2. Penicillin Binding and Inactivation of Enzyme Activity.- 3. Localization of PBPs.- 4. Labeling of PBPs in Live, Growing Bacteria.- 5. Selective Affinity of PBPs for Various ?-Lactams.- 6. Selective Morphological Effects.- VI. Penicillin-Sensitive Enzymes in Cell Wall Synthesis.- 1. Penicillin-Sensitive Enzymes as PBPs.- D. Physiological Consequences of ?-Lactam Inhibition.- I. Search for the Killing Targets.- II. Labeling of PBPs in Live Bacteria.- III. In Vivo Labeling of PBPs in Pneumococci.- IV. Dynamic Experiments with the Labeling of PBPs in Growing Pneumococci.- V. PBP Alterations in Intrinsically ?-Lactam-Resistant Bacteria.- VI. Several Physiologically Important PBPs in Pneumococci.- E. Variations in the Physiological Effects of Penicillins.- I. The Single Target - Unbalanced Growth Model.- II. From Inhibited Enzyme to Inhibited Target Cell.- III Inhibition of Growth, Loss of Viability, Lysis.- IV. The PBPs of Penicillin-Tolerant Bacteria.- V. Penicillin-Induced Death, Without Lysis (Group A Streptococci).- VI. Reversible Growth-Inhibitory Effect of Penicillin.- VII. Penicillin Tolerance in Bacteria with Suppressed Murein Hydrolase Activity.- VIII. Penicillin-Induced Lysis and Death in E. coli.- IX. How and Why Does Penicillin Cause Cell Wall Degradation?.- X. Possible Causes of Penicillin-Induced Cell Wall Degradation in E. coli.- XI. Penicillin-Induced Lysis and Natural Inhibitors of Autolysis.- XII. Attempts to Define the Events Responsible for the Triggering of Autolytic Activity in Pneumococci.- F. Environmental Factors That Modulate the Antibacterial Effects of Penicillin.- I. Protection Against the Lytic (and Cidal) Effects by Alteration of the pH of the Medium.- II. The Effect of Exogenous Murein Hydrolases on Penicillin-Treated Tolerant Bacteria.- III. Synergistic Bactericidal Action of Penicillin and Human Polymorphonuclear White Blood Cells (PMN).- IV. Inhibition of Penicillin-Induced Lysis by Extracellular Lipids and Lipoteichoic Acids.- V. Penicillin-Induced Release of Cell Surface Components into the Medium.- VI. Phenotypic Tolerance in Nongrowing Cells.- G. Conclusion.- References.- 3 Strain Improvement and Preservation of ?-Lactam-Producing Microorganisms.- A. Introduction.- B. Distribution of ?-Lactam Antibiotics and Related Metabolites in Nature.- C. Strain Improvement Programs in Commercially Important ?-Lactam Fermentation Organisms.- I. Mutation and Enhanced Penicillin Formation in P. chrysogenum.- II. Mutagenesis and Yield Improvement in the Cephalosporin C Organism, Acremonium chrysogenum.- III. Rational Screening or Selection for Improved Mutants or Mutants Producing Modified ?-Lactam Antibiotics.- 1. Mutants Screened Directly on Agar Plates.- 2. Selection of Mutants for Resistance to Toxic Antibiotic Precursors or Analogs of Precursors.- 3. Selection of Mutants Resistant to Metallic Ions.- 4. Isolation of Specific Morphological Mutants of A. chrysogenum.- 5. Use of Auxotrophic Strains or Revertants of Auxotrophic Strains.- 6. Mutational Biosynthesis and New Biosynthetic ?-Lactams.- D. Actinomycetes Producing New ?-Lactam Antibiotics.- I. Cephamycins (7-Methoxycephalosporins).- 1. Cephamycin Fermentations.- 2. Improvement in Strains of Nocardia lactamdurans.- II. Nocardicins.- 1. Strain Improvement.- 2. Nocardicin A Fermentation.- III. Clavulanic Acid.- IV. Hydroxyethylclavam.- V. Thienamycin.- VI. Olivanic Acids.- VII. PS-5 and Related Carbapenems.- VIII. C-19393 S2 and H2.- IX. Carpetimycins.- E. Unicellular Bacteria Producing Sulfazecins and Related Structures.- F. Maintenance and Long-Term Preservation of Strains of Penicillium chrysogenum and Acremonium chrysogenum.- I. Studies with P. chrysogenum.- II. Studies with A. chrysogenum.- References.- 4 Genetics of ?-Lactam-Producing Fungi.- A. Introduction.- B. Aspergillus nidulans.- I. The Parasexual Cycle.- II. The Genetics of Penicillin Production.- C. Penicillium chrysogenum.- I. Early Studies.- II. Later Studies.- D. Cephalosporium acremonium.- E. Recombination Between Naturally Incompatible Fungi.- References.- 5 Genetics of ?-Lactam-Producing Actinomycetes.- A. Introduction.- B. ?-Lactam Antibiotics and the Actinomycetales.- C. Streptomyces Genetics.- I. Plasmids in Streptomyces.- II. Plasmids in ?-Lactam-Producing Streptomyces.- D. Antibiotic Production in Actinomycetes.- I. Unstable Genetic Systems in Streptomyces Which do not Involve Plasmids.- II. Protoplast Fusion and Streptomyces.- III. Transformation and Streptomyces.- IV. Restriction and Modification Systems in Streptomyces.- V. Genetic Engineering and Streptomyces.- E. The Genetics of ?-Lactam Antibiotics and the Future.- References.- 6 Biosynthesis of ?-Lactam Antibiotics.- A. Introduction.- B. Hydrophobic ?-Lactam Antibiotics.- I. Biosynthetic Precursors.- II. Terminal Biosynthetic Reaction.- C. Hydrophilic ?-Lactam Antibiotics.- I. Early Biosynthetic Steps.- II. Formation of the Bicyclic Ring Structure.- III. Epimerization of Isopenicillin N to Penicillin N.- IV. Conversion of Penicillin N to Cephalosporin C.- V. Formation of Additional Cephalosporins by Actinomycetes.- D. Antibiotic Production by Pairs of Blocked Mutants.- E. Novel ?-Lactam Antibiotics.- I. Fungal Products.- II. Actinomycete Products.- III. Products of Unicellular Bacteria.- References.- 7 Regulation of Biosynthesis of ?-Lactam Antibiotics.- A. Introduction.- B. Carbon Catabolite Regulation.- I. Regulation of the Biosynthesis of Fungal ?-Lactams by Glucose.- II. Carbon Catabolite Regulation of the Biosynthesis of ?-Lactams by Actinomycetes.- C. Nitrogen Metabolite Regulation.- D. Regulation at the Level of Sulfur Metabolism.- E. Lysine Metabolism and Antibiotic Biosynthesis.- I. Control by Lysine of the Biosynthesis of Fungal ?-Lactams.- II. Lysine Effect in Actinomycetes.- F. Control of ?-Lactam Specific Enzymes at the Level of Secondary Metabolism.- I. Possible Control Mechanisms at the Tripeptide Synthetase Level.- 1. Control of the Cyclization of the Tripeptide.- 2. Control of the Ring-Expansion System.- II. Control of Penicillin Acyltransferase.- III. Regulation of Late Enzymes in Cephalosporin and Cephamycin Biosynthesis.- G. End-Product Regulation.- H. Summary and Future Outlook.- References.- 8 Biochemical Engineering and ?-Lactam Antibiotic Production.- A. Introduction.- B. Penicillin Fermentation - Current Status.- C. Growth Monitoring and Control - Method of Approach.- I. Formulation of a Realistic Medium.- II. Growth Monitoring.- 1. Empirical Correlations.- 2. Physiological …