Antibiotics: Containing the Beta-Lactam Structure

375 Pages·1983·33.59 MB·English

by  E. P. Abraham (auth.)

Handbook of
Experimental Pharmacology
Continuation of Handbuch der experimentellen Pharmakologie
Vol. 6711
Editorial Board
G. V. R Born, London· A. Farah, Rensselaer, New York
H. Herken, Berlin· A. D. Welch, Memphis, Tennessee
Advisory Board
S. Ebashi . E. G. Erdos· V. Erspamer· U. S. von Eiller· W. S. Feldberg
G. B. Koelle· M. Rocha e Silva· J. R. Vane· P. G. Waser
Antibiotics
Containing the Beta-Lactam Structure
Part I
Contributors
E. P. Abraham· Y.Aharonowitz· C. Ball· B. G. Christensen
A. L. Demain· R. P. Elander· R. Kirby. J. E Martin· R. D. Miller
D.-G. Mou· N. Neuss· T. N. Salzmann· E. O. Stapley· A.Tomasz
S. B. Zimmerman
Editors
A. L. Demain and N. A. Solomon
Springer-Verlag Berlin Heidelberg New York Tokyo 1983
Professor Dr. ARNOLD L. DEMAIN
Ms. NADINE A. SOLOMON
Fermentation Microbiology Laboratory
Department of Nutrition and Food Science
Massachusetts Institute of Technology
Cambridge, MA 02139/USA
With 83 Figures
ISBN-13:978-3-642-81968-1 e-ISBN-13:978-3-642-81966-7
DOl: 10.1007/978-3-642-81966-7
Library of Congress Cataloging in Publication Data. Main entry under title: Antibiotics containing the beta-Iactam
structure. (Handbook of experimental pharmacology; v. 61, pt. 1-) Includes index. I. Antibiotics - Synthesis. 2. Beta
lactaIll/lses. 3. Fungi - Genetics. [DNLM: I. Antibiotics - Pharmacodynamics. 2. Beta·lactamases - Pharmaco
dynamics. WI HA51L v. 61/QV 350 A62935] QP905.H3 vol. 61, pt. I, etc. 615'.1s 82-19689 [QD315] [541.7'6]
This work is subject to copyright. All rights are reserved, whether the whole or part of the material is concerned,
specifically those of translation, reprinting, re-use of illustrations, broadcasting, reproduction by photocopying
machine or similar means, and storage in data banks. Under § 54 of the German Copyright Law where copies are
made for other than private use, a fee is payable to "Verwertungsgesellschaft Wort", Munich.
© by Springer·Veriag Berlin Heidelberg 1983
Softcover reprint of the hardcover 1st edition 1983
The use of registered names, trademarks, etc. in this publication does not imply, even in the absence of a specific
statement, that such names are exempt from the relevant protective laws and regulations and therefore free for
general use.
Product Liability: The publisher can give no guarantee for information about drug dosage and application thereof
contained in this book. In every individual case the respective user must check its accuracy by consulting other
pharmaceutical literature.
2122/3130-543210
Preface
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.
Considering the level of excitement in this area, we felt that this would be the
right time for the leaders in the field to survey past and present research,
development, and clinical applications of p-Iactams and prospects for future
progress. We were pleasantly surprised that so many busy people agreed to give up
their time to contribute to this project. The result is this volume in two parts
describing all aspects of p-Iactam antibiotics.
Cambridge ARNOLD L. DEMAIN
NADINE A. SOLOMON
List of Contributors
Sir E. P. ABRAHAM, Sir William Dunn School of Pathology, University of Oxford,
South Parks Road, Oxford OXl 3RE, Great Britain
Dr. Y. AHARONOWITZ, Department of Microbiology, The George S. Wise Faculty
of Life Sciences, Tel-Aviv University, Tel-Aviv, Israel
Dr. C. BALL, Squibb Institute for Medical Research, Biological Process
Development, E. R. Squibb & Sons, Inc., Georges Road, New Brunswick,
NJ 08903jUSA
Dr. B. G. CHRISTENSEN, Merck Sharp & Dohme Research Laboratories,
P.O. Box 2000, Rahway, NJ 07065jUSA
Professor Dr. A. L. DEMAIN, Fermentation Microbiology Laboratory, Department
of Nutrition and Food Science, Massachusetts Institute of Technology,
Cambridge, MA 02139jUSA
Dr. R. P. ELANDER, Fermentation Research and Development, Bristol-Myers Co.,
Industrial Division, P.O. Box 657, Syracuse, NY 1320IjUSA
Dr. R. KIRBY, University of Cape Town, Department of Microbiology,
Rondebosch 7700, South Africa
Professor Dr. J. F. MARTIN, Department of Microbiology, Faculty of Biology,
University of Leon, Leon, Spain
Dr. R. D. MILLER, Eli Lilly & Co., P.O. Box 685, Lafayette, IN 47902jUSA
Dr. D.-G. MOD, Research Laboratories, Eastman Kodak Company, Kodak Park,
Rochester, NY 14650jUSA
Dr. N. NEDSS, Lilly Research Laboratories, Eli Lilly & Co., Indianapolis,
IN 46205/USA
Dr. T. N. SALZMANN, Merck Sharp & Dohme Research Laboratories,
Rahway, NJ 07065(USA
VIII List of Contributors
Dr. E. O. STAPLEY, Merck Sharp & Dohme Research Laboratories, Department of
Basic Macrobiological Research, P.O. Box 2000, Rahway, NJ 07065/USA
Dr. A. TOMASZ, The Rockefeller University, 1230 York Avenue, New York,
NY 10021/USA
Dr. S. B. ZIMMERMAN, Merck Sharp & Dohme Research Laboratories,
Department of Basic Macrobiological Research, P.O. Box 2000, Rahway,
NJ 07065/USA
Contents
CHAPTER 1
History of P-Lactam Antibiotics. E. P. ABRAHAM
A. The Past Fifty Years . . . . . . . . . . . . . . . . . .. 1
I. Fleming's Discovery. . . . . . . . . . . . . . . .. 1
II. Discovery of the Therapeutic Power of Penicillin in Systemic
Infections . . . . . . . . . . . . . . . . . . 2
III. Large-Scale Production . . . . . . . . . . . . 2
IV. Wartime Interest in Penicillin in Europe and Japan 3
V. Isolation, Structure, and Synthesis. . . . . . 4
VI. Penicillin-Resistant Bacteria . . . . . . . . . . 5
VII. 6-Aminopenicillanic Acid and New Penicillins. . . 6
VIII. 7-Aminocephalosporanic Acid and the Cephalosporins . 7
IX. New fJ-Lactam Compounds . . 9
X. Biosynthesis . . . . . . . . . 9
XI. Mode of Action and Resistance. 10
B. The Future 11
References . . . . . . . . . . . . . . 13
CHAPTER 2
Mode of Action of p-Lactam Antibiotics - A Microbiologist's View. A. TOMASZ.
With 17 Figures
A. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . 15
I. Mode of Action Studies: Benefits for Basic and Applied Sciences. 15
II. Mode of Action of Penicillin: A Multilevel Problem . . . .. 16
B. Journey of the Extracellular Antibiotic to the Intracellular Targets 17
I. Extracellular Barriers . . . . . . . . . . . . 17
II. Barriers in the Bacterial Envelope. . . . . . . . . . . 17
III. The Outer Membrane of Gram-Negative Bacteria. . . . 18
IV. The End of the Journey: Arrival at the Plasma Membrane 19
C. The Biochemical Targets of fJ-Lactam Antibiotics. . . . . . . 20
I. Selective Toxicity of fJ-Lactams. . . . . . . . . . . . 20
II. Localization of Radioactively Labeled Penicillin in Bacteria. 23
III. Morphological and Biochemical Effects of Penicillin . 23
IV. Penicillin-Sensitive Enzymes . . . . . . . . . . . . . . 25
x Contents
1. Molecular Basis of Specificity . . . . . . . . . . 26
2. Studies with Model Substrates and Model Enzymes . 29
V. Penicillin-Binding Proteins (PBPs). . . . . . . . . . 35
1. Enzymatic Activity of PBPs with Model Substrates . 35
2. Penicillin Binding and Inactivation of Enzyme Activity 36
3. Localization of PBPs . . . . . . . . . . . . . 37
4. Labeling of PBPs in Live, Growing Bacteria . . . 38
5. Selective Affinity of PBPs for Various p-Lactams . 40
6. Selective Morphological Effects . . . . . . . 41
VI. Penicillin-Sensitive Enzymes in Cell Wall Synthesis 46
1. Penicillin-Sensitive Enzymes as PBPs . . . 50
D. Physiological Consequences of p-Lactam Inhibition. 51
I. Search for the Killing Targets . . . . . 51
II. Labeling of PBPs in Live Bacteria. . . . . . 53
III. In Vivo Labeling of PBPs in Pneumococci . . 54
IV. Dynamic Experiments with the Labeling of PBPs in Growing
Pneumococci. . . . . . . . . . . . . . . . . . . . . 55
V. PBP Alterations in Intrinsically p-Lactam-Resistant Bacteria 57
VI. Several Physiologically Important PBPs in Pneumococci 57
E. Variations in the Physiological Effects of Penicillins. . 60
I. The Single Target - Unbalanced Growth Model. 60
II. From Inhibited Enzyme to Inhibited Target Cell 61
III. Inhibition of Growth, Loss of Viability, Lysis. . 61
IV. The PBPs of Penicillin-Tolerant Bacteria. . . . 63
V. Penicillin-Induced Death, Without Lysis (Group A Streptococci). 64
VI. Reversible Growth-Inhibitory Effect of Penicillin . . . . . . . 64
VII. Penicillin Tolerance in Bacteria with Suppressed Murein Hydrolase
Activity . . . . . . . . . . . . . . . . . . . . . . . . . 66
VIII. Penicillin-Induced Lysis and Death in E. coli . . . . . . . . . 68
IX. How and Why Does Penicillin Cause Cell Wall Degradation? 69
X. Possible Causes of Penicillin-Induced Cell Wall Degradation in
E. coli. . . . . . . . . . . . . . . . . . . . . . . . . . 71
XI. Penicillin-Induced Lysis and Natural Inhibitors of Autolysis . . 72
XII. Attempts to Define the Events Responsible for the Triggering of
Autolytic Activity in Pneumococci. . . . . . . . . . . . .' . 73
F. Environmental Factors That Modulate the Antibacterial Effects of
Penicillin . . . . . . . . . . . . . . . . . . . . . . . . . . . 74
I. Protection Against the Lytic (and Cidal) Effects by Alteration of
the pH of the Medium. . . . . . . . . . . . . . . . . . . 74
II. The Effect of Exogenous Murein Hydrolases on Penicillin-Treated
Tolerant Bacteria. . . . . . . . . . . . . . . . . . . . . 75
III. Synergistic Bactericidal Action of Penicillin and Human Polymor
phonuclear White Blood Cells (PMN) . . . . . . . . . . . . 75
IV. Inhibition of Penicillin-Induced Lysis by Extracellular Lipids and
Lipoteichoic Acids . . . . . . . . . . . . . . . . . . . . 75
V. Penicillin-Induced Release of Cell Surface Components into the
Medium. . . . . . . . . . . . . . . . . . . . . . . . . 76
Contents XI
VI. Phenotypic Tolerance in Nongrowing Cells. 76
G. Conclusion 78
References . . . . . . . . . . . . . . . . . . . 84
CHAPTER 3
Strain Improvement and Preservation of p-Lactam-Producing Microorganisms.
R. P. ELANDER. With 9 Figures
A. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . 97
B. Distribution of p-Lactam Antibiotics and Related Metabolites in Nature. 99
C. Strain Improvement Programs in Commercially Important p-Lactam
Fermentation Organisms . . . . . . . . . ........... 109
I. Mutation and Enhanced Penicillin Formation in P. chrysogenum. 110
II. Mutagenesis and Yield Improvement in the Cephalosporin C
Organism, Acremonium chrysogenum. . . . . . . . . . . . . 112
III. Rational Screening or Selection for Improved Mutants or Mutants
Producing Modified p-Lactam Antibiotics . . . . . . . . . . 114
1. Mutants Screened Directly on Agar Plates. . . . . . . . . 115
2. Selection of Mutants for Resistance to Toxic Antibiotic Pre-
cursors or Analogs of Precursors . . . . . . . . . . . . . 115
3. Selection of Mutants Resistant to Metallic Ions. . . . __ . . 116
4. Isolation of Specific Morphological Mutants of A. chrysogenum 117
5. Use of Auxotrophic Strains or Revertants of Auxotrophic
Strains . . . . . . . . . . . . . . . . . . . . .. 117
6. Mutational Biosynthesis and New Biosynthetic p-Lactams 118
D. Actinomycetes Producing New p-Lactam Antibiotics 119
I. Cephamycins (7-Methoxycephalosporins). . . . . . 119
1. Cephamycin Fermentations . . . . . . . . . . 121
2. Improvement in Strains of Nocardia lactamdurans . 123
II. Nocardicins . . . . . . . . 123
1. Strain Improvement . . . 124
2. Nocardicin A Fermentation 126
III. Clavulanic Acid. . . 129
IV. Hydroxyethylclavam 129
V. Thienamycin . . . . 130
VI. Olivanic Acids . . . 130
VII. PS-5 and Related Carbapenems . 131
VIII. C-19393 S2 and H2 . . . . . . 133
IX. Carpetimycins . . . . . . . . 134
E. Unicellular Bacteria Producing Sulfazecins and Related Structures 134
F. Maintenance and Long-Term Preservation of Strains of Penicillium
chrysogenum and Acremonium chrysogenum 135
I. Studies with P. chrysogenum 136
II. Studies with A. chrysogenum 138
References . . . . . . . . . . . . 140
XII Contents
CHAPTER 4
Genetics of /l-Lactam-Producing Fungi. C. BALL. With 4 Figures
A. Introduction. . . . . . 147
B. Aspergillus nidulans. . . . . . . . . . 147
I. The Parasexual Cycle . '.' . . . . 148
II. The Genetics of Penicillin Production 149
C. Penicillium chrysogenum . 150
I. Early Studies. . . . . 151
II. Later Studies. . . . . 153
D. Cephalosporium acremonium 157
E. Recombination Between Naturally Incompatible Fungi 159
References . . . . . . . . . . . . . . . . . . . . . 160
CHAPTER 5
Genetics of fJ-Lactam-Producing Actinomycetes. R. KIRBY. With 4 Figures
A. Introduction. . . . . . . . . . . . . . . 163
B. fJ-Lactam Antibiotics and the Actinomycetales 165
C. Streptomyces Genetics . . . . . . . . . . 167
I. Plasmids in Streptomyces . . . . . . . 171
II. Plasmids in fJ-Lactam-Producing Streptomyces 175
D. Antibiotic Production in Actinomycetes. . . . . 176
I. Unstable Genetic Systems in Streptomyces Which do not Involve
Plasmids . . . . . . . . . . . . 177
II. Protoplast Fusion and Streptomyces . . . . . . . . 178
III. Transformation and Streptomyces . . . . . . . . . 179
IV. Restriction and Modification Systems in Streptomyces. 180
V. Genetic Engineering and Streptomyces . . . . . 181
E. The Genetics of fJ-Lactam Antibiotics and the Future. 183
References . . . . . . . . . . . . . . . . . . . . . 184
CHAPTER 6
Biosynthesis of fJ-Lactam Antibiotics. A. L. DEMAIN. With 6 Figures
A. Introduction. . . . . . . . . . . 189
B. Hydrophobic fJ-Lactam Antibiotics . 191
I. Biosynthetic Precursors . . . . 191
II. Terminal Biosynthetic Reaction 197
C. Hydrophilic fJ-Lactam Antibiotics . 198
I. Early Biosynthetic Steps. . . . 200
II. Formation of the Bicyc1ic Ring Structure 201
III. Epimerization of Isopenicillin N to Penicillin N 203
IV. Conversion of Penicillin N to Cephalosporin C . 203
V. Formation of Additional Cephalosporins by Actinomycetes 206
D. Antibiotic Production by Pairs of Blocked Mutants. . . . . . 208