The tetracyclines have an illustrious history as therapeutic agents which dates back over half a century. Initially discovered as an antibiotic in 1947, the four ringed molecule has captured the fancy of chemists and biologists over the ensuing decades. Of further interest, as described in the chapter by George Armelagos, tetracyclines were already part of earlier cultures, 1500-1700 years ago, as revealed in traces of drug found in Sudanese Nubian mummies. The diversity of chapters which this book presents to the reader should illus trate the many disciplines which have examined and seen benefits from these fascinating natural molecules. From antibacterial to anti-inflammatory to anti autoimmunity to gene regulation, tetracyclines have been modified and redesigned for various novel properties. Some have called this molecule a biol ogist's dream because of its versatility, but others have seen it as a chemist's nightmare because of the synthetic chemistry challenges and "chameleon-like" properties (see the chapter by S. Schneider).

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.

Among the many who serve in the United States Armed Forces and who are deployed to distant locations around the world, myriad health threats are encountered. In addition to those associated with the disruption of their home life and potential for combat, they may face distinctive disease threats that are specific to the locations to which they are deployed. U.S. forces have been deployed many times over the years to areas in which malaria is endemic, including in parts of Afghanistan and Iraq. Department of Defense (DoD) policy requires that antimalarial drugs be issued and regimens adhered to for deployments to malaria-endemic areas. Policies directing which should be used as first and as second-line agents have evolved over time based on new data regarding adverse events or precautions for specific underlying health conditions, areas of deployment, and other operational factors At the request of the Veterans Administration, Assessment of Long-Term Health Effects of Antimalarial Drugs When Used for Prophylaxis assesses the scientific evidence regarding the potential for long-term health effects resulting from the use of antimalarial drugs that were approved by FDA or used by U.S. service members for malaria prophylaxis, with a focus on mefloquine, tafenoquine, and other antimalarial drugs that have been used by DoD in the past 25 years. This report offers conclusions based on available evidence regarding associations of persistent or latent adverse events.

Following the successful and proven concept used in "Bioactive Heterocyclic Compound Classes" by the same editors, this book is the first to present approved pharmaceutical and agrochemical compounds classified by their carboxylic acid functionality in one handy volume. Each of the around 40 chapters describes one or two typical syntheses of a specific compound class and provides concise information on the history of development, mode of action, biological activity and field of application, as well as structure-activity relationships. In addition, similarities and differences between pharmaceuticals and agrochemicals are discussed in the introduction. Written by a team of experts in the field, this is a useful reference for researchers in academia and chemical or pharmaceutical companies working in the field of total synthesis and natural product chemistry, drug development, and crop protection research.

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.

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.