The Tetracyclines: (78 Handbook of Experimental Pharmacology)

The history of antibiotics may weIl have begun with the ancient Sudanese-Nubian civilization (see Chapter 1, "Historical Introduction"), but this volume reflects a more contemporary appraisal of the antibiotic era. We have compiled a comprehensive review of the tetracyclines which includes all the major sub- divisions of these chemically important and clinically useful antibiotics. There can be little doubt about the contribution of antibiotics to both the increase in human life span and the alleviation of much human suffering. The tetracyclines are still playing an important role in these areas and will continue to do so in the foreseeable future. We hope this volume will be an important contribution to a better under- standing of the chemistry, biochemistry, and medical aspects of tetracycline antibiotics. We are indebted to the individual authors who have given so much of their time and effort in the preparation of the chapters. Pearl River, NY J OSEPH J. HLA VKA Ocean Gate, NJ JAMES H. BOOTHE Contents CHAPTER 1 Historical Introduction. J. H. BOOTHE and J. J. HLAVKA References. 3 CHAPTER 2 Fermentation and Mutational Development of the Tetracyclines J. J. GOODMAN A. Introduction 5 B. The Producing Microorganisms . 6 I. Morphology and Ultrastructure 6 11. Mutation and Strain Selection 8 111. Cosynthesis. 13 The Fermentation Process 14 C. I. Inoculum 14 11. Contamination 16 Complex Media. 18 111. IV. Synthetic Media. 27 V. Stimulators and Inhibitors 30 Directed Fermentations 32 VI.

Table of Contents:
1 Historical Introduction.- References.- 2 Fermentation and Mutational Development of the Tetracyclines.- A. Introduction.- B. The Producing Microorganisms.- I. Morphology and Ultrastructure.- II. Mutation and Strain Selection.- III. Cosynthesis.- C. The Fermentation Process.- I. Inoculum.- II. Contamination.- III. Complex Media.- IV. Synthetic Media.- V. Stimulators and Inhibitors.- VI. Directed Fermentations.- D. Fermentation Technology.- I. Aeration.- II. Temperature.- E. Concluding Remarks.- References.- 3 Structure Determination and Total Synthesis of the Tetracyclines.- A. Introduction.- B. Structure Determination.- I. Oxytetracycline.- II. Chlortetracycline.- III. Tetracycline.- IV. 6-Demethyltetracyclines.- V. 2-Acetyl-2-decarboxamidotetracyclines.- VI. 6-Methylenetetracyclines.- VII. 6-Deoxytetracyclines and 7- and 9-Substituted 6-Deoxytetracyclines.- VIII. Oxytetracycline Esters.- IX. Tetracycline Metal Chelates.- C. Partial Synthesis from Derivatives.- I. 4-Epitetracyclines.- II. 12a-Deoxytetracyclines.- III. 5a,6-Anhydrotetracyclines and 5a(11a)-Dehydrotetracyclines.- IV. 4-Oxotetracyclines-4,6-hemiketals and Tetracycloxides.- D. Total Synthesis of Tetracycline Derivatives and Incomplete Syntheses.- I. Aromatic A-Ring Compounds.- II. Analogues Lacking the Dimethylamino Group or Other Key Functionality.- E. Total Synthesis of 6-Demethyl-6-deoxytetracycline.- I. Woodward; Conover et al.- II. Muxfeldt et al.- F. Total Synthesis of Fermentation Tetracyclines.- I. Tetracycline: Shemyakin et al.- II. Chlortetracyclines: Muxfeldt et al.- III. Oxytetracycline: Muxfeldt et al.- G. Total Synthesis of Tetracycline Analogues.- I. dl-7-Chloro-6-deoxytetracyclines.- II. dl-8-Hydroxy-6-demethyl-6-deoxytetracycline.- III. dl-6-Thiatetracycline.- References.- 4 Biosynthesis of the Tetracyclines.- A. Introduction.- B. Production Strains.- I. Taxonomy.- II. Growth.- III. Genetics.- C. Building Units of Tetracyclines.- D. The Biosynthetic Pathway of Tetracyclines.- I. The Origin of the Tricyclic Nonaketide.- II. Transformations of the Tricyclic Nonaketide.- III. Transformation of the Tricyclic Decaketide.- IV. Genetic Loci Responsible for the Biosynthesis of Tetracyclines.- E. Regulation of the Biosynthesis of Tetracyclines.- E. Regulation of the Biosynthesis of Tetracyclines.- I. Saccharide Metabolism.- II. Formation of Malonyl CoA.- III. Energy Metabolism.- F. Biosynthesis of Macromolecules and the Production of Tetracyclines.- I. Nucleic Acid Metabolism.- II. Interaction of Tetracycline Antibiotics with Ribosomes.- III. Protein Synthesis.- IV. High-Phosphorylated Nucleotides.- G. Conclusion.- References.- 5 Chemical Modification of the Tetracyclines.- A. Introduction.- B. Semisynthetic Tetracyclines.- I. Modifications at the C1 and C3 Positions.- II. Modifications at the C2 Position.- III. Modifications at the C4 Position.- IV. Modifications at the C5 Position.- V. Modifications at the C5a Position.- VI. Modifications at the C6 Position.- VII. Modifications at the C7 and C9 Positions.- VIII. Modifications at the C11 and C12 Positions.- IX. Modifications at the C11a Position.- X. Modifications at the C12a Position.- XI. Structure-Activity Relationships.- C. Totally Synthetic Unnatural Tetracyclines.- I. General Synthetic Pathways.- II. Anhydrotetracyclines.- III. (+-) B-Nortetracyclines.- IV. Modification at the C2 Position: (+-)-4-Amino-7-chloro-2-N-methylcarbonyl-2-decarbonyl-4-dedimethylamino-6-demethyl-6-deoxytetracyclines.- V. Modifications at the C5a and C6 Positions: (+-)-7-Chloro-6 deoxytetracyclines and (+- )-7-Chloro-6-demethyl-6-deoxytetracyclines.- VI. Modification at the C7 Position: (+-)-7-Methoxy-6-demethyl-6-deoxytetracyclines.- VII. Modification at the C8 Position: (+-)-8-Hydroxy-6-demethoxy-6-deoxytetracyclines.- VIII. Modifications at the C5a Position: (+-)-5a-Methyl-6-demethyl-6-deoxytetracyclines.- IX. Modifications at the C6 Position: 6-Heterotetracyclines.- D. Overall Structure-Activity Relationships.- I. Structural Requirements for Activity.- II. Structural Features Essential for Activity.- III. Effect of Structural Variation on Pharmacokinetics.- IV. Summary.- V. Conclusions.- References.- 6 Mode of Action of the Tetracyclines and the Nature of Bacterial Resistance to Them.- A. Introduction.- B. Mode of Action of the Tetracyclines: Studies Before 1964.- I. Introduction.- II. Early Studies (1948-1953) on the Mode of Action of Tetracyclines.- III. Studies (1953-1 Historical Introduction.- References.- 2 Fermentation and Mutational Development of the Tetracyclines.- A. Introduction.- B. The Producing Microorganisms.- I. Morphology and Ultrastructure.- II. Mutation and Strain Selection.- III. Cosynthesis.- C. The Fermentation Process.- I. Inoculum.- II. Contamination.- III. Complex Media.- IV. Synthetic Media.- V. Stimulators and Inhibitors.- VI. Directed Fermentations.- D. Fermentation Technology.- I. Aeration.- II. Temperature.- E. Concluding Remarks.- References.- 3 Structure Determination and Total Synthesis of the Tetracyclines.- A. Introduction.- B. Structure Determination.- I. Oxytetracycline.- II. Chlortetracycline.- III. Tetracycline.- IV. 6-Demethyltetracyclines.- V. 2-Acetyl-2-decarboxamidotetracyclines.- VI. 6-Methylenetetracyclines.- VII. 6-Deoxytetracyclines and 7- and 9-Substituted 6-Deoxytetracyclines.- VIII. Oxytetracycline Esters.- IX. Tetracycline Metal Chelates.- C. Partial Synthesis from Derivatives.- I. 4-Epitetracyclines.- II. 12a-Deoxytetracyclines.- III. 5a,6-Anhydrotetracyclines and 5a(11a)-Dehydrotetracyclines.- IV. 4-Oxotetracyclines-4,6-hemiketals and Tetracycloxides.- D. Total Synthesis of Tetracycline Derivatives and Incomplete Syntheses.- I. Aromatic A-Ring Compounds.- II. Analogues Lacking the Dimethylamino Group or Other Key Functionality.- E. Total Synthesis of 6-Demethyl-6-deoxytetracycline.- I. Woodward; Conover et al.- II. Muxfeldt et al.- F. Total Synthesis of Fermentation Tetracyclines.- I. Tetracycline: Shemyakin et al.- II. Chlortetracyclines: Muxfeldt et al.- III. Oxytetracycline: Muxfeldt et al.- G. Total Synthesis of Tetracycline Analogues.- I. dl-7-Chloro-6-deoxytetracyclines.- II. dl-8-Hydroxy-6-demethyl-6-deoxytetracycline.- III. dl-6-Thiatetracycline.- References.- 4 Biosynthesis of the Tetracyclines.- A. Introduction.- B. Production Strains.- I. Taxonomy.- II. Growth.- III. Genetics.- C. Building Units of Tetracyclines.- D. The Biosynthetic Pathway of Tetracyclines.- I. The Origin of the Tricyclic Nonaketide.- II. Transformations of the Tricyclic Nonaketide.- III. Transformation of the Tricyclic Decaketide.- IV. Genetic Loci Responsible for the Biosynthesis of Tetracyclines.- E. Regulation of the Biosynthesis of Tetracyclines.- E. Regulation of the Biosynthesis of Tetracyclines.- I. Saccharide Metabolism.- II. Formation of Malonyl CoA.- III. Energy Metabolism.- F. Biosynthesis of Macromolecules and the Production of Tetracyclines.- I. Nucleic Acid Metabolism.- II. Interaction of Tetracycline Antibiotics with Ribosomes.- III. Protein Synthesis.- IV. High-Phosphorylated Nucleotides.- G. Conclusion.- References.- 5 Chemical Modification of the Tetracyclines.- A. Introduction.- B. Semisynthetic Tetracyclines.- I. Modifications at the C1 and C3 Positions.- II. Modifications at the C2 Position.- III. Modifications at the C4 Position.- IV. Modifications at the C5 Position.- V. Modifications at the C5a Position.- VI. Modifications at the C6 Position.- VII. Modifications at the C7 and C9 Positions.- VIII. Modifications at the C11 and C12 Positions.- IX. Modifications at the C11a Position.- X. Modifications at the C12a Position.- XI. Structure-Activity Relationships.- C. Totally Synthetic Unnatural Tetracyclines.- I. General Synthetic Pathways.- II. Anhydrotetracyclines.- III. (+-) B-Nortetracyclines.- IV. Modification at the C2 Position: (+-)-4-Amino-7-chloro-2-N-methylcarbonyl-2-decarbonyl-4-dedimethylamino-6-demethyl-6-deoxytetracyclines.- V. Modifications at the C5a and C6 Positions: (+-)-7-Chloro-6 deoxytetracyclines and (+- )-7-Chloro-6-demethyl-6-deoxytetracyclines.- VI. Modification at the C7 Position: (+-)-7-Methoxy-6-demethyl-6-deoxytetracyclines.- VII. Modification at the C8 Position: (+-)-8-Hydroxy-6-demethoxy-6-deoxytetracyclines.- VIII. Modifications at the C5a Position: (+-)-5a-Methyl-6-demethyl-6-deoxytetracyclines.- IX. Modifications at the C6 Position: 6-Heterotetracyclines.- D. Overall Structure-Activity Relationships.- I. Structural Requirements for Activity.- II. Structural Features Essential for Activity.- III. Effect of Structural Variation on Pharmacokinetics.- IV. Summary.- V. Conclusions.- References.- 6 Mode of Action of the Tetracyclines and the Nature of Bacterial Resistance to Them.- A. Introduction.- B. Mode of Action of the Tetracyclines: Studies Before 1964.- I. Introduction.- II. Early Studies (1948-1953) on the Mode of Action of Tetracyclines.- III. Studies (1953-1964) Identifying Protein Synthesis as the Primary Target for the Action of Tetracyclines.- C. Current Views on the Nature of Bacterial Protein Synthesis.- I. Introduction.- II. Structure of Ribosomes.- III. Initiation of Protein Synthesis.- IV. Recognition of Internal Codons.- V. Peptide Bond Formation and Translocation.- VI. Termination of Protein Synthesis.- D. Effects of Tetracyclines on Protein Synthesis in Prokaryotes.- I. Effects of Tetracyclines on the Synthesis of Protein In Vivo.- II. Effects of Tetracyclines on the Synthesis of Protein In Vitro.- E. Binding of Tetracyclines to Macromolecules.- I. Introduction.- II. Binding of Tetracyclines to Ribosomes.- F. Molecular Basis of Tetracycline Action.- G. Relation Between Structure and Activity in the Tetracyclines.- H. Effects of Growth in the Presence of Low Tetracycline Concentrations on Microbial Metabolism.- I. Selective Toxicity of the Tetracyclines.- I. Introduction.- II. Entry of Tetracyclines into Eukaryotic Cells.- III. Effect of Tetracyclines on Eukaryotic Protein Synthesis.- IV. Selective Toxicity of the Tetracyclines - The Apparent Paradox Explained.- J. Transport of Tetracyclines into Bacteria.- I. Introduction.- II. Transport of Tetracyclines Across the Gram-Negative Outer Membrane.- III. Transport of Tetracyclines Across the Cytoplasmic Membrane of Gram-Positive and-Negative Bacteria.- IV. Fluorescence Assay for Tetracycline Transport -)-4-Amino-7-chloro-2-N-methylcarbonyl-2-decarbonyl-4-dedimethylamino-6-demethyl-6-deoxytetracyclines.- V. Modifications at the C5a and C6 Positions: (+-)-7-Chloro-6 deoxytetracyclines and (+- )-7-Chloro-6-demethyl-6-deoxytetracyclines.- VI. Modification at the C7 Position: (+-)-7-Methoxy-6-demethyl-6-deoxytetracyclines.- VII. Modification at the C8 Position: (+-)-8-Hydroxy-6-demethoxy-6-deoxytetracyclines.- VIII. Modifications at the C5a Position: (+-)-5a-Methyl-6-demethyl-6-deoxytetracyclines.- IX. Modifications at the C6 Position: 6-Heterotetracyclines.- D. Overall Structure-Activity Relationships.- I. Structural Requirements for Activity.- II. Structural Features Essential for Activity.- III. Effect of Structural Variation on Pharmacokinetics.- IV. Summary.- V. Conclusions.- References.- 6 Mode of Action of the Tetracyclines and the Nature of Bacterial Resistance to Them.- A. Introduction.- B. Mode of Action of the Tetracyclines: Studies Before 1964.- I. Introduction.- II. Early Studies (1948-1953) on the Mode of Action of Tetracyclines.- III. Studies (1953-1964) Identifying Protein Synthesis as the Primary Target for the Action of Tetracyclines.- C. Current Views on the Nature of Bacterial Protein Synthesis.- I. Introduction.- II. Structure of Ribosomes.- III. Initiation of Protein Synthesis.- IV. Recognition of Internal Codons.- V. Peptide Bond Formation and Translocation.- VI. Termination of Protein Synthesis.- D. Effects of Tetracyclines on Protein Synthesis in Prokaryotes.- I. Effects of Tetracyclines on the Synthesis of Protein In Vivo.- II. Effects of Tetracyclines on the Synthesis of Protein In Vitro.- E. Binding of Tetracyclines to Macromolecules.- I. Introduction.- II. Binding of Tetracyclines to Ribosomes.- F. Molecular Basis of Tetracycline Action.- G. Relation Between Structure and Activity in the Tetracyclines.- H. Effects of Growth in the Presence of Low Tetracycline Concentrations on Microbial Metabolism.- I. Selective Toxicity of the Tetracyclines.- I. Introduction.- II. Entry of Tetracyclines into Eukaryotic Cells.- III. Effect of Tetracyclines on Eukaryotic Protein Synthesis.- IV. Selective Toxicity of the Tetracyclines - The Apparent Paradox Explained.- J. Transport of Tetracyclines into Bacteria.- I. Introduction.- II. Transport of Tetracyclines Across the Gram-Negative Outer Membrane.- III. Transport of Tetracyclines Across the Cytoplasmic Membrane of Gram-Positive and-Negative Bacteria.- IV. Fluorescence Assay for Tetracycline Transport - A Cautionary Tale.- V. Transport of Tetracycline Across the Bacterial Cytoplasmic Membrane: Conclusion.- K. Plasmid-Determined Resistance to the Tetracyclines.- I. Occurrence of Plasmids in Natural Bacterial Isolates.- II. Tetracycline-Resistance Determinants: Transposable and Amplifiable Sequences.- III. Genetic Comparison of Regions Coding for Tetracycline Resistance.- IV. Proteins Synthesized by Tetracycline-Resistance Determinants: General Nature of the Proteins and Organization of the Genes Which Encode Them.- V. Mode of Action of Membrane-Located Resistance Proteins.- VI. Membrane Architecture in Relation to the Binding and Function of Plasmid-Determined Tetracycline-Resistance Proteins.- VII. Membrane-Located Resistance Proteins: Specific Properties and Comparisons Between Proteins Encoded by Different Determinants.- VIII. Gene Copy Number and Decreased Tetracycline Accumulation.- IX. Are the Membrane-Located Resistance Proteins That Mediate Efflux the Only Products Responsible for Resistance?.- X. Therapeutic Consequences of Tetracycline-Resistance Gene Amplification.- XI. Use of the Fluorescence Assay for Tetracycline for Studies on Plasmid-Determined Resistance.- XII. Inducibility of Plasmid-Determined Resistance to Tetracycline.- XIII. Expression of Tetracycline Resistance in Escherichia coli Renders Cells Hypersensitive to Lipophilic Chelating Agents.- XIV. Epidemiology of Tetracycline Resistance.- XV. Origin of Plasmid-Located Tetracycline-Resistance Genes.- L. Chromosomal Mutation to Tetracycline Resistance.- M. Conclusions.- References.- 7 Clinical Uses of the Tetracyclines.- A. Antimicrobial Activity.- B. Clinical Uses.- C. Treatment of First Choice.- D. Effective Alternative Treatment.- E. Treatment of Clinical Syndromes.- F. Ineffective Treatment.- G. Dosage and Duration of Therapy.- References.- 8 Nonmedical Uses of the Tetracyclines.- A. Historical.- B. Growth Promotion and Improved Feed Efficiency in Livestock.- I. Poultry.- II. Cattle.- III. Horses.- IV. Swine.- C. Disease Prevention Effects of Chlortetracycline and Oxytetracycline.- I. Poultry.- II. Ducks.- III. Chickens.- IV. Cattle.- V. Sheep.- VI. Swine.- D. Public Health Considerations.- I. Epidemiology of Antibiotic Resistance.- II. Salmonella.- III. Tissue Residues.- E. Government Restrictions.- I. Great Britain and Europe.- II. United States.- III. Far East.- References.