Antibiotics: A Multidisciplinary Approach

283 Pages·1995·7.452 MB·English

by  Giancarlo Lancini, Francesco Parenti, Gian Gualberto Gallo (auth.)

Antibiotics
A Multidisciplinary
Approach
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
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 978-1-4757-9202-7 ISBN 978-1-4757-9200-3 (eBook)
DOI 10.1007/978-1-4757-9200-3
1. Antlbiotics. I. Parenti, Francesco. II. Gallo, Gian
Cualberto. III. Titl~.
[DNLM: 1. Antibiotics--pharmacology. 2. Antibiotics--metabolism.
3. Structure-Actlvity Relationship. 4. Drug Resistance, Microbial.
av 350 L249a 19951
RM267.L33 1995
615' .329--dc20
DNLM/DLC
for Llbrary of Congress 95-11625
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 978-1-4757-9202-7
© 1995 Springer Science+Business Media New York
Originally published by Plenum Press, New York in 1995
Softcover reprint of the bardeover 1st edition 1995
10 9 8 7 6 5 4 3 2 1
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
Preface
Fifty years after the introduction of penicillin into therapeutic use,
antibiotics are among the most widely used drugs, not only in the treat
ment of human ailments but also in veterinary practice, in agriculture,
andin animal husbandry. Furthermore, they areessential tools for re
search 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: genet
ics, molecular biology, industrial microbiology, medical microbiology,
chemistry of natural products, and analytical chemistry.
In teaching undergraduate and postgraduate courses, it became ap
parent that a book did not exist presenting the facts and the basic con
cepts of this broad and varied subject. During many years of experience
in an industrial laboratory dedicated to the research of new antibiotics~
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
vi Preface
need. Same years later, updated translations in English and in Russian
were published, and, to celebrate the fiftieth anniversary of the intro
duction of penicillin into medical use, a new ltalian edition, completely
revised in content and format, was published in 1993. The present ver
sion, 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 re
vised 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
Contents
1. The Antibiotics: An Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
1.1. Definition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
1.2. Chemical Nature . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
1.3. Producing Microorganisms . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
1.4. Biosynthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
1.5. Activity and Resistance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
1.6. Mechanism of Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
1.7. Chemotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
1.8. Chemical Modifications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
1. 9. Principal Classes of Antibiotics . . . . . . . . . . . . . . . . . . . . . . . 8
2. The Activity of Antibiotics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
2.1. Definition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
2.2. Determination of the Activity . . . . . . . . . . . . . . . . . . . . . . . . 16
2.3. Determination of the Concentration of Antibiotics
(Assay) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
2.4. Miniaturization and Automation . . . . . . . . . . . . . . . . . . . . . . 35
vii
viii Contents
3. The Mechanism of Action of Antibiotics . . . . . . . . . . . . . . . . . . . 37
3.1. General Aspects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38
3.2. Methods of Study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
3.3. Inhibitors of Cell Wall Synthesis . . . . . . . . . . . . . . . . . . . . . . 42
3.4. Inhibitors of Replication and Transcription of Nucleic
Acid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54
3.5. Inhibitors of Protein Synthesis . . . . . . . . . . . . . . . . . . . . . . . 62
3.6. Inhibitors of Cell Membrane Functions . . . . . . . . . . . . . . . . 70
3.7. Antimetabolites . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74
3.8. Selectivity of Antibiotic Action . . . . . . . . . . . . . . . . . . . . . . . 78
4. Resistance of Microorganisms to Antibiotics . . . . . . . . . . . . . . . . 85
4.1. General Aspects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85
4.2. Biochemical Bases of Resistance . . . . . . . . . . . . . . . . . . . . . . 89
4.3. Genehe Aspects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94
4.4. Interesting Examples of Bacterial Resistance . . . . . . . . . . . 100
5. Activity of Antibiotics in Relation to Their Structure . . . . . . . . 107
5.1. Introducbon . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108
5.2. ß-Lactam Antibiotics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 110
5.3. Tetracyclines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 137
5.4. Aminoglycosides (Aminocyclitols) . . . . . . . . . . . . . . . . . . . . 142
5.5. Macrolides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 152
5.6. Ansamycins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 160
5.7. Peptide Antibiotics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 166
5.8. Glycopeptide Antibiotics (Dalbaheptides) . . . . . . . . . . . . . . 168
5.9. Antitumor Antibiotics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 170
5.10. Miscellaneous Antibiotics . . . . . . . . . . . . . . . . . . . . . . . . . . . 173
6. Biosynthesis and Genetics of Antibiotic Production . . . . . . . . . 179
6.1. Methods of Study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 180
6.2. Biosynthetic Reactions and Pathways . . . . . . . . . . . . . . . . . 184
6.3. Transformation of Primary Metabolites into Antibiotics
or Antibiotic Moieties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 186
6.4. Antibiotics Derived from Polyketide Synthesis . . . . . . . . . 193
6.5. Antibiotics Derived from Polymerization of Amino
Acids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 199
6.6. Isoprenoid Antibiotics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 205
6.7. Oligosaccharide Antibiotics . . . . . . . . . . . . . . . . . . . . . . . . . . 206
6.8. Genetics of Antibiotic Production . . . . . . . . . . . . . . . . . . . . . 209
Contents ix
7. The Search for and Development of New Antibiotics 215
7.1. The Search for New Antibiotics .. .. .. .. .. .. .. .. .. .. .. 216
7.2. Development of an Antibiotic from the Labaratory to
the Clinic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 225
7.3. Development of an Antibiotic from the Labaratory to
the Manufacturing Process . . . . . . . . . . . . . . . . . . . . . . . . . . . 233
8. The Use of Antibiotics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 243
8.1. Chemotherapy of Infectious Diseases . . . . . . . . . . . . . . . . . 243
8.2. Uses Other Than Human Pharmacology . . . . . . . . . . . . . . 250
8.3. Antibiotics as Research Tools . . . . . . . . . . . . . . . . . . . . . . . . . 253
9. Antibiotics and Producer Organisms . . . . . . . . . . . . . . . . . . . . . . 255
9 .1. Classes of Antibiotics and Taxonomie Position of
Producing Organisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 256
9.2. Paradox: How to Avoid Suicide . . . . . . . . . . . . . . . . . . . . . . . 258
9.3. Hypothesis about the Functions of Antibiotics in
Producing Organisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 260
10. Further Reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 265
Index ...................................................... 273
1
Chapter
The Antibiolies
An Overview
The aim of this chapter is to provide the reader with basic definitions
and general information on antibiotics in order to facilitate an under
standing of the following chapters, where various aspects of the
biology and chemistry of antibiotics are described in a more specific
way.
Thus, this chapter can be considered an expanded summary of
the book; it give the picture of the whole before presenting its com
ponent parts.
1.1. Definition
Antibiofies are low-molecular-weight microbial metabolites that at low con
centrations inhibit the growth of other microorganisms. A low-molecular
weight substance is a molecule with a defined chemical structure having
a relative mass of at most a few thousand. We do not include among the
1