Antibiotics A Multidisciplinary Approach

Transcription

1 Antibiotics A Multidisciplinary Approach

2 Antibiolies A Multidisciplinary Approach Giancarlo Lancini Marion Merrell Dow Research Institute (MMDRI) Lepetit Research Center Gerenzano (Varese), Italy Francesco Parenti Marion Merrell Dow Europe AG Horgen, Switzerland and Gian Gualberto Gallo Formerly of Marion Merrell Dow Research Institute (MMDRI) Lepetit Research Center Gerenzano (Varese), Italy Springer Science+Business Media, LLC

3 Llbrary of Congress Catalog1ng-1n-Pub11cat1on Data Lanclni, Giancarlo. Anti biotlcs a multidlscipllnary approach I Giancarlo Lanclni, Francesco Parenti, and Gian Gualberto Gallo. p. cm. Includes bibllographlcal references and Index. ISBN ISBN (ebook) DOI / Antlbiotics. I. Parenti, Francesco. II. Gallo, Gian Cualberto. III. T i t l ~. [DNLM: 1. Antibiotics--pharmacology. 2. Antibiotics--metabolism. 3. Structure-Actlvity Relationship. 4. Drug Resistance, Microbial. av 350 L249a RM267.L '.329--dc20 DNLM/DLC for Llbrary of Congress CIP Publication history First edition: Biochimica e Biologie degli Antibiotici, G. C. Lancini and F. Parenti, ISEDI, Milan, Italy (1977) First edition-english translation: Antibiolies-An Integrated View, G. C. Lancini and F. Parenti, Springer-Verlag, New York (1982) First edition-russian translation: Antibiotiki, G. C. Lancini and F. Parenti, MIR Moscow, USSR (1985) Second edition: Biochimica e Biologia delgi Antibiotici, G. C. Lancini, F. Parenti, and G. G. Gallo, Salerno, ltaly (1993) ISBN Springer Science+Business Media New York Originally published by Plenum Press, New York in 1995 Softcover reprint of the bardeover 1st edition All rights reserved No part of this book may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, microfilming, recording, or otherwise, without written permission from the Publisher

4 Preface Fifty years after the introduction of penicillin into therapeutic use, antibiotics are among the most widely used drugs, not only in the treatment of human ailments but also in veterinary practice, in agriculture, andin animal husbandry. Furthermore, they areessential tools for research in genetics, microbiology, and molecular biology. Production of antibiotics involves a diverse group of professionals: the microbiologist, the fermentation technologist, the bioengineer, and the chemist. Research and development of a new antibiotic requires the collaboration among experts in even more numerous disciplines: genetics, molecular biology, industrial microbiology, medical microbiology, chemistry of natural products, and analytical chemistry. In teaching undergraduate and postgraduate courses, it became apparent that a book did not exist presenting the facts and the basic concepts of this broad and varied subject. During many years of experience in an industrial laboratory dedicated to the research of new a n t i b i o t i c s ~ we realized that our young colleagues, specialized in one discipline, often had a poor knowledge of the general aspects of the research in which they were involved and of the problems brought about by the development and the use of antibiotics. This book was born eighteen years ago to fulfill, at least in part, this V

5 vi Preface need. Same years later, updated translations in English and in Russian were published, and, to celebrate the fiftieth anniversary of the introduction of penicillin into medical use, a new ltalian edition, completely revised in content and format, was published in The present version, which is essentially based on the last ltalian edition, has been greatly modified from the first English edition, so that it is practically a new book. We would like to believe that reading this book may also interest medical doctors, who, either in laboratories or clinics, use antibiotics and are curious to know more about the mental and practical processes that Iead from the isolation of a microorganism from a soil sample to a tablet or a vial ready to use. The understanding of the broader "biology of antibiotics" may also be of help in the proper use of these drugs. Many research colleagues in both the industrial and the academic worlds have helped conceive and realize this book. We thank them and acknowledge their contribution and the greater merit for its potential usefulness. We are particularly indebted to Dr. Mark Fisher, St. George's Hospital, London, and Stefano Donadio, of our Laboratories, for their criticisms and suggestions, and to Ms. Suzanne Ress, who patiently revised the English style. As for the first edition, we wish to dedicate this book to Piero Sensi, discoverer of rifamycins, teacher, and friend. G. C. Lancini, F. Parenti, and G. G. Gallo

6 Contents 1. The Antibiotics: An Overview Definition Chemical Nature Producing Microorganisms Biosynthesis Activity and Resistance Mechanism of Action Chemotherapy Chemical Modifications Principal Classes of Antibiotics The Activity of Antibiotics Definition Determination of the Activity Determination of the Concentration of Antibiotics (Assay) Miniaturization and Automation vii

7 viii Contents 3. The Mechanism of Action of Antibiotics General Aspects Methods of Study Inhibitors of Cell Wall Synthesis Inhibitors of Replication and Transcription of Nucleic Acid Inhibitors of Protein Synthesis Inhibitors of Cell Membrane Functions Antimetabolites Selectivity of Antibiotic Action Resistance of Microorganisms to Antibiotics General Aspects Biochemical Bases of Resistance Genehe Aspects Interesting Examples of Bacterial Resistance Activity of Antibiotics in Relation to Their Structure Introducbon ß-Lactam Antibiotics Tetracyclines Aminoglycosides (Aminocyclitols) Macrolides Ansamycins Peptide Antibiotics Glycopeptide Antibiotics (Dalbaheptides) Antitumor Antibiotics Miscellaneous Antibiotics Biosynthesis and Genetics of Antibiotic Production Methods of Study Biosynthetic Reactions and Pathways Transformation of Primary Metabolites into Antibiotics or Antibiotic Moieties Antibiotics Derived from Polyketide Synthesis Antibiotics Derived from Polymerization of Amino Acids Isoprenoid Antibiotics Oligosaccharide Antibiotics Genetics of Antibiotic Production

8 Contents ix 7. The Search for and Development of New Antibiotics The Search for New Antibiotics Development of an Antibiotic from the Labaratory to the Clinic Development of an Antibiotic from the Labaratory to the Manufacturing Process The Use of Antibiotics Chemotherapy of Infectious Diseases Uses Other Than Human Pharmacology Antibiotics as Research Tools Antibiotics and Producer Organisms Classes of Antibiotics and Taxonomie Position of Producing Organisms Paradox: How to Avoid Suicide Hypothesis about the Functions of Antibiotics in Producing Organisms Further Reading Index