Antibiotics: Containing the Beta-Lactam Structure

ISBN-13: 9783642819681 / Angielski / Miękka / 2011 / 360 str.

Arnold L. Demain;Nadine A. Solomon

Opis

It is quite amazing that the oldest group of medically useful antibiotics, the p-Iactams, are still providing basic microbiologists, biochemists, and clinicians with surprises over 50 years after Fleming's discovery of penicillin production by Penicillium. By the end of the 1950s, the future of the penicillins seemed doubtful as resistant strains of Staphylococcus aureus began to increase in hospital populations. However, the development of semisynthetic penicillins provided new structures with resistance to penicillinase and with broad-spectrum activity. In the 1960s, the discovery of cephalosporin C production by Cephalosporium and its conversion to valuable broad-spectrum antibiotics by semisynthetic means excited the world of chemotherapy. In the early 1970s, the 40-year-old notion that p-lactams were produced only by fungi was destroyed by the discovery of cephamycin production by Streptomyces. Again this basic discovery was exploited by the development of the semisynthetic cefoxitin, which has even broader activity than earlier p-lactams. Later in the 1970 s came the discoveries of nocardicins from Nocardia, clavulanic acid from Streptomyces, and the carbapenems from Streptomyces. Now in the 1980s we learn that p-lactams are produced even by unicellular bacteria and that semisynthetic derivatives of these monobactams may find their way into medicine. Indeed, the future of the prolific p-lactam family seems brighter with each passing decade.

Spis treści

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 Model — Respiratory Quotient.- 3. Carbon-Balancing Equation.- III. Growth Control in Fed-Batch Fermentation.- 1. Control Strategy.- 2. Manipulation of Cell Growth Curve by On-Line Controlled Glucose Feed.- D. Effect of Growth on Penicillin Production.- E. Effect of the Use of Corn-Steep Liquor.- F. Maintenance Demand as a Fermentation Variable.- I. Calculation of Maintenance Demand for Sugar.- II. Reduction of Maintenance Demand Through Strain Improvement.- III. Reduction of Maintenance Demand Through Process Improvement and Its Implication.- G. Overall Conversion Yield of Glucose to Penicillin- Ppis.- H. Summary.- I. New Insight into Fermentation Kinetics.- II. Proposal of a Working Methodology for Process Improvement.- References.- 9 Screening for New ?-Lactam Antibiotics.- A. Introduction.- B. Rationale for Screening of ?-Lactam Antibiotics.- I. Mode of Action.- II. Potency and Spectrum.- III. Chemical Alterability.- IV. Potentiation of Other Antibiotics.- C. Finding ?-Lactam-Producing Microorganisms.- I. Discovery of Fungi as Producers of ?-Lactams.- II. Discovery of Actinomycetes as Producers of ?-Lactams.- 1. World-Wide Search for Antibiotic-Producing Microorganisms.- 2. Development of Culture Isolation Techniques.- III. Discovery of Bacteria as Producers of ?-Lactams.- D. Screening Systems Which Detect ?-Lactams.- I. Biospectrum and Physicochemical Data Comparisons.- 1. Penicillin N.- 2. Cephamycins.- II. ?-Lactamase Inhibition.- 1. Clavulanic Acid.- 2. Olivanic Acids.- 3. PS-5, -6, and -7.- 4. Carpetimycins.- III. ?-Lactam Supersensitive Bacterial Mutants.- 1. The Nocardicins.- 2. Deacetoxycephalosporin C.- 3. PS-5.- 4. Sulfazecin and Isosulfazecin.- IV. Screening for Bacterial Cell Wall Inhibitors.- 1. Cephamycins, Epithienamycins, and Thienamycins.- 2. Azureomycin.- V. Screening of Penicillin N-Producing Cultures.- 1. Deacetoxycephalosporin C.- E. Future Trends.- F. A Hypothetical Screening Model.- References.- 10 High-Performance Liquid Chromatography of ?-Lactam Antibiotics.- A. Introduction.- B. Penicillin Antibiotics.- I. 6-Aminopenicillanic Acid (6-APA).- II. Amoxicillin (Clamoxyl).- III. Ampicillin (Penbritin).- IV. Carbenicillin.- V. Penicillin G.- VI. Penicillin V.- VII. Sulbenicillin.- VIII. Concluding Remarks.- C. Cephalosporin Antibiotics.- I. 7-Aminocephalosporanic Acid (7-ACA).- II. Cefaclor.- III. Cefamandole.- IV. Cefazolin.- V. Cefoxitin.- VI. Ceftizoxime.- VII. Cephalexin.- VIII. Cephaloglycin.- IX. Cephaloridine.- X. Cephalosporin C.- XI. Cephalothin.- XII. Cephapirin.- XIII. Cephradine.- XIV. Concluding Remarks.- D. Other ?-Lactam Compounds.- I. Nocardicin A and B.- II. Clavulanic Acid.- III. Thienamycin.- IV. Olivanic Acids.- E. Oxy-?-L actams.- F. Concluding Remarks.- References.- 11 Strategy in the Total Synthesis of ?-Lactam Antibiotics.- A. Introduction.- B. ?-Lactam Closure.- C. 2+2 Annelations.- D. Monocyclic ?-Lactam Antibiotics.- E. Examples Involving Prior Construction of the Azetidinone.- F. Penicillin Total Synthesis — Sheehan.- G. Cefoxitin Total Synthesis — Merck.- H. Nocardicin Total Synthesis — Wasserman.- I. Total Synthesis of (±)-Clavulanic Acid — Beecham.- J. Cephalosporin C Total Synthesis — Woodward.- K. Penicillin Total Synthesis — Baldwin.- L. Synthesis of the Penem Nucleus — Woodward.- M. Total Synthesis of (+)-Thienamycin — Merck.- N. Conclusion.- References.