The Biology of Beta-Lactam Antibiotics. Volume 3: Biochemistry

422 Pages·1982·22.08 MB·English

by  Robert Morin

Chemistry and Biology
of ß-Lactam Antibiotics
Volume 3 The Biology of ß-Lactam Antibiotics
Edited by
ROBERT B. MORIN
Bristol Laboratories
Syracuse, New York
MARVIN GORMAN
Eli Lilly and Company
Indianapolis, Indiana
1982
@
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United Kingdom Edition published by
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Library of Congress Cataloging in Publication Data
Main entry under title:
Chemistry and biology of B-lactam antibiotics.
Includes bibliographies and index.
1. Antîbiotics--Synthesis. 2. Penicillin. 3· Cepha-
losporin. 4. Lactams. 5. Chemistry, Pharmaceutical.
I. Morin, Robert B. II. Gorman, Marvin.
QD375.C+7 615'·329 82-6638
ISBN O-I2-5O6303-2 (v.3)
PRINTED IN THE UNITED STATES OF AMERICA
82 83 84 85 9 8 7 6 5 4 3 2 1
Contributors
Numbers in parentheses indicate the pages on which the authors' contributions begin.
Hatsuo Aoki (83), Research Laboratories, Fujisawa Pharmaceutical Com-
pany, Ltd., Osaka, 532 Japan
Karen Bush (155), Squibb Institute for Medical Research, Princeton,
New Jersey 08540
Christopher M. Cimarusti (339), Squibb Institute for Medical Research,
Princeton, New Jersey 08540
Lolita Daneo-Moore (303), Department of Microbiology and Immunol-
ogy, Temple University, Philadelphia, Pennsylvania 19140
Richard P. Elander (83), Industrial Division, Bristol-Myers Company,
Syracuse, New York 13201
Robert B. Kammer (287), Lilly Research Laboratories, Eli Lilly and
Company, Indianapolis, Indiana 46285
William H. Koster (339), Squibb Institute for Medical Research, Prince-
ton, New Jersey 08540
Thomas D. McDowell (303), Department of Microbiology and Immu-
nology, Temple University, Philadelphia, Pennsylvania 19140
Norbert Neuss (I), Lilly Research Laboratories, Eli Lilly and Company,
Indianapolis, Indiana 46285
Stephen W. Queener (1), Lilly Research Laboratories, Eli Lilly and
Company, Indianapolis, Indiana 46285
Gerald D. Shockman (303), Department of Microbiology and Immunol-
ogy, Temple University, Philadelphia, Pennsylvania 19140
Jack L. Strominger (209), The Biological Laboratories, Harvard Uni-
versity, Cambridge, Massachusetts 02138
Richard B. Sykes (155, 339), Squibb Institute for Medical Research,
Princeton, New Jersey 08540
David J. Waxman (209), Department of Biochemistry and Molecular
Biology, Harvard University, Cambridge, Massachusetts 02138
William Wong (303), Department of Microbiology and Immunology, Tem-
ple University, Philadelphia, Pennsylvania 19140
IX
Preface
The increasing therapeutic role of /3-lactam antibiotics and the discovery of
significant new members of this series through synthetic chemical or fermenta-
tion screening programs has led to an exponential growth during the last decade
in the literature describing the chemistry and biology of these substances. The
present volume, the third of a three-part treatise, attempts to present recent
scientific information concerning this broad class of antibiotics. Previous ex-
tended monographs on the subject have focused exclusively on penicillins or
cephalosporins with relevant chemistry. The present volumes cover advances in
these two members of the class and in addition, the chemistry and biology of a
series of new synthetic or biosynthetic /3-lactam antibiotics.
Volume 1 is devoted to reports of recent studies on the chemical, biological,
physicochemical and computational aspects of the properties of penicillins
and cephalosporins; including an extensive review of the cephamycins (7-
methoxycephalosporins). Volume 2 is concerned exclusively with classes of
nontraditional /3-lactam antibiotics. These are defined as /3-lactams having an-
tibacterial or /3-lactamase-inhibitory properties, but differing from penicillins or
cephalosporins in any of the following ways: (a) lacking a fused ring system,
(b) having the penicillin or cephalosporin ring system modified in ring size or a
heteroatom substitution; or (c) lacking the amide side chain common to the
established /3-lactam antibiotics. Volume 3 concentrates on general biological
properties of /3-lactam antibiotics and includes the biosynthesis, fermentation,
mode of inhibition and killing of bacteria, mechanisms of enzymatic degrada-
tion, and a clinical perspective of use. Also included in this volume is a descrip-
tion of recently described monobactam antibiotics and an appendix that provides
data relevant to material in all volumes and several important experimental
procedures.
The momentous discovery 40 years ago of the therapeutic effectiveness of
penicillin in the treatment of certain bacterial infections stimulated a number of
important basic biological studies. These studies are related to the clinical role of
penicillin, to the biological and biochemical basles with which these agents inter-
fere with bacterial metabolism, and to the nature of the biosynthesis of the natural
members of the series from simple primary metabolites. The general topics
xi
Xll PREFACE
presented in Volume 3 represent reports on these subjects.
An early difficulty involved in the use of these agents was the problem of
development of a practical fermentation procedure that would allow production
of large quantities of antibiotics. The progress in developing this methodology
and a description of newer fermentation techniques are presented in Chapter 2.
At this time all /3-lactam antibiotics in clinical use derive from fermentation
products. The knowledge of the biosynthetic sequence, particularly of penicillins
and cephalosporins, is detailed in Chapter 1. Early work had shown that ß-lactam
antibiotics affect bacterial cell wall synthesis; the status of knowledge concerning
the biochemical aspects of these events is discussed in Chapter 4. The relation-
ship between inhibition of cell wall biosynthesis and lethality to the bacterial cell
is more specifically addressed in Chapter 6. Workers recognized the existence of
a bacterial enzyme that destroys penicillin before the /3-lactam structure of
penicillin was firmly established. This enzyme was identified as a ß-lactamase,
and later the existence of a related series of enzymes with differing substrate
specificities was found to be widespread. The description of these enzymes, their
importance in the development of newer agents, and their inactivation is pre-
sented in Chapter 3. The ready availability of the natural product, coupled with a
better understanding of biological properties and the changing clinical needs, has
led to a rapid expansion of the /3-lactam products available for clinical use. A
perspective of the clinical role of /3-lactam antibiotics is given in Chapter 5.
Although great progress in understanding the topics included in this volume
has been achieved since the initial work with penicillin, these areas still represent
the greatest research challenge in this field. Future studies will provide the
information and inspiration for the development of new therapeutic agents. There
will be a greater cognizance of the role j3-lactam antibiotics play in the control of
the overall bacterial infectious disease process.
R. B. Morin
M. Gorman
Contents of Other Volumes
VOLUME 1: PENICILLINS AND CEPHALOSPORINS
The Chemistry of Penicillin Sulfoxide
Robin D. G. Cooper and Gary A. Koppel
Cephalosporin Antibiotics Prepared by Modifications at the C-3 Position
Stjepan Kukolja and Robert R. Chauvette
Cephamycin Antibiotics
Eric M. Gordon and Richard B. Sykes
Antimicrobial and Pharmacokinetic Properties of Newer Penicillins
and Cephalosporins
/. Alan Webber and William J. Wheeler
Theoretical and Physicochemical Studies on ß-Lactam Antibiotics
Donald B. Boyd
Index
VOLUME 2: NONTRADITIONAL ß-LACTAM
ANTIBIOTICS
Partial Synthesis of Nuclear Analogs of Cephalosporins
Wataru Nagata, Masayuki Narisada, and Tadashi Yoshida
Total Synthesis of Penicillins, Cephalosporins, and Their Nuclear Analogs
Kenneth G. Holden
Nocardicins
Takashi Kamiya, Hatsuo Aoki and Yasuhiro Mine
y
The Chemistry of Thienamycin and Other Carbapenem Antibiotics
Ronald W. Ratcliffe and Georg Albers-Schönberg
Xlll
XIV CONTENTS OF OTHER VOLUMES
The Penems
Ivan Ernest
Clavulanic Acid
Peter C. Cherry and Christopher E. Newall
Index
1
The Biosynthesis of ß-Laetam Antibiotics
S. W. QUEENER AND NORBERT NEUSS
I. Introduction 2
II. Steps Common to Biosynthesis of Penicillins, Cephalosporins,
and 7a-Methoxycephalosporins 4
A. Formation of 8-(L-a-Aminoadipyl)-L-cysteinyl-D-valine and Its Role in
Biosynthesis of Penicillins and Cephalosporins 5
B. Conversion of ô-(L-a-Aminoadipyl)-L-cysteinyl-D-valine to
Isopenicillin N 12
C. Intermediates and Mechanisms in the Formation of Isopenicillin N . 14
III. The Enzymatic Conversion of Isopenicillin N to
Pénicillium-Type Penicillins 26
A. The Role of Isopenicillin N in the Biosynthesis of
Penicillium-Type Penicillins 27
B. Monosubstituted Acetic Acid : Coenzyme A Ligase 27
C. Cell-Free Reaction Linking Isopenicillin N to
Penicillium-Type Penicillins 27
D. Isopenicillin N Amidolyase (6-APA Forming) 28
E. AcylCoA : 6-APA Acyltransferase 30
F. AcylCoA : Isopenicillin N Acyltransferase 31
G. Gratuitous Activities of AcylCoA : 6-APA Acyltransferase . . .. 31
H. MSSA : CoA Ligase, Isopenicillin N Amidolyase (6-APA Forming),
and AcylCoA : 6-APA Acyltransferase 35
I. Penicillin Acylase and AcylCoA : 6-APA Acyltransferase . . .. 35
J. A Model for the Enzymatic Conversion of Isopenicillin N
to Penicillium-Type Penicillins 37
IV. Mechanism of Penicillin G Excretion 39
V. Biosynthesis of Cephalosporins and 7a-Methoxycephalosporins . . .. 40
A. Conversion of Isopenicillin N to Penicillin N 40
B. Conversion of Penicillin N to Deacetoxycephalosporin C . . . . 40
C. Possible Intermediates in the Conversion of Penicillin N
to Deacetoxycephalosporin C 43
The Chemistry and Biology of Copyright © 1982 by Academic Press, Inc.
ß-Lactam Antibiotics, Vol. 3 All rights of reproduction in any form reserved.
ISBN 0-12-506303-2
1
2 S. W. QUEENER AND NORBERT NEUSS
D. Conversion of Deacetoxycephalosporin C to
Deacetylcephalosporin C 49
VI. Synthesis of Cephalosporins and 7 α-Methoxycephalosporins . . .. 52
A. Conversion of Deacetylcephalosporin C to Cephalosporin C . . . 52
B. Conversion of Deacetylcephalosporin C to
O-Carbamoylcephalosporin C 54
C. 7-Hydroxylation and 7-O-Methylation of Cephalosporins . . .. 55
D. Acylation at 3-Hydroxymethyl in Ceph-3-em-4-carboxylic Acids . . 58
E. Displacement of 3-Hydroxymethyl Substituents by Sulfur
Metabolites 61
F. Metabolites Derived from Penicillins, Cephalosporins,
and 7a-Methoxycephalosporins 62
VII. Genes Associated with Conversion of Primary Metabolites to Penam and
Ceph-3-em Antibiotics 64
VIII. Distribution of Cephalosporins, 7a-Methoxycephalosporins,
and Penicillium-Type Penicillins 67
IX. New Classes of ß-Lactam Antibiotics and Their Biosyntheses . . .. 67
A. Nocardicins 68
B. Clavam Antibiotics 69
C. The l-Carbapen-2-em Antibiotics 71
X. The Relationship of ß-Lactam Bond Formation in Penam, Clavam,
l-Carbapen-2-em, and Nocardicin Antibiotics 72
XI. The Future: Significant Questions and New Possibilities 73
References 75
I. Introduction
The ever-increasing number of recognized ß-lactam-containing natural
products necessitates some introductory remarks. Many compounds that
contain the ß-lactam ring (1) possess antimicrobial activity. These nat-
urally occurring substances are substituted as in structure 2. A new class
of naturally occurring ß-lactam antibiotics termed "monobactams" has
structure 2a. (See Chapter 7 for chemistry and biosynthesis.) They are
antibiotics because of their capacity to inhibit cell wall synthesis in
bacteria. In this chapter we consider the biosynthesis of ß-lactam
antibiotics.
~b ^c
RL R
Rd
Rf
(1) C02H
(2) (2a)
As used here, the terms penicillin, cephalosporin, 7a-methoxycepha-
losporin (Volume 1, Chapter 3), and nocardicin (Volume 2, Chapter 3)
refer to ß-lactam compounds characterized by structures 3-6.
THE BIOSYNTHESIS OF ß-LACTAM ANTIBIOTICS 3
Q H H H 0 H H H H
il I
R-C-N CH3 Ra-C-Nfc-f Y+ VIHHH
'CH3 CH2Rb
ΐΓ 'C02H C02H
(3) (4)
Penicillin Cephalosporin
CHo
I 3 OH
0 H Q H /=\\*cQ H H H H r =\
R.-Cli -NII >SVLH Ra0- \\ //-C"C-N
• -N^^CH2Rb
C02H H t02H
(6)
(5)
7a- Methoxycephalosporin Nocardicin
The terms penam, cepham, ceph-3-em, clavam, and l-carbapen-2-em
refer to the bicyclic ring structures 7-11, respectively.
L>
/Γ~ N
(7) (8) (9)
'enani Cepham Ceph-3-em
CO
0
(10)
(11)
Clavam l-Ca rbapen-2-em
Use of the terms penam, cepham, ceph-3-em, clavam, and 1-carbapen-
2-em refers to classes of ß-lactam antibiotics that share the same bicyclic
ring structure.
Pénicillium chrysogenum incorporates many monosubstituted acetic
acids (RCH C0 H, where R is a nonpolar moiety) into penicillins so that
2 2
the acid becomes the acyl substituent attached at the C-6 nitrogen in the
penicillin via an amide linkage. These acids can be present endogenously
or added exogenously. We refer to such substances as Penicillium-type
penicillins. These penicillins are soluble in nonpolar organic solvents at
low pH. The best known of these Penicillium-type penicillins are pen-
icillin G (benzylpenicillin) (12) and penicillin V (phenoxymethylpeniciUin)
(13).