Emerging Targets in Antibacterial and Antifungal Chemotherapy

606 Pages·1992·4.87 MB·English

by  Akira Imada

Emerging Targets in Antibacterial and
Antifungal Chemotherapy
Emerging Targets in Antibacterial and
Antifungal Chemotherapy
Edited by
Joyce A. Sutcliffe and
Nafsika H. Georgopapadakou
Springer-Science+Business Media, B. V.
il:) 1992 Springer Science+Business Media Dordrecht
Origina\ly published by Routledge, Chapman & Hali, Inc. in 1992
Softcover reprint ofthe hardcover lst edition 1992
AII rights reserved. No put of this book may be reprinted or reproduced or utilized in any form or
by any electronic, mechanical or other rneans, now known or hereafter invented, including photocopy
ing and recording, or by an information storage or retrieval system, without permission in writing
from the publishers.
Ubrary of Congress Cataloging in Publication Data
Emerging targets in antibacterial and antifungal chemotherapy I
[edited by] Joyce A. Sutcliffe, Nafsika H. Georgopapadakou.
p. cm.
Includes bibliographical references and index.
ISBN 978-1-4613-6440-5 ISBN 978-1-4615-3274-3 (eBook)
DOI 10.1007/978-1-4615-3274-3
1. Pbarmaceutical microbiology. 2. Antibiotics. 3. Microbial
sensitivity tests. 1. Sutcliffe, Joyce A. II. Georgopapadakou,
Nafsika H., 1950-
QR46.S.E44 1991
615'.329--dc20 91-15763
CIP
British Ubrary cataloguing in publication data also available.
To our parents: Tasso and Elli Georgopapadakou
Ralph and Hazel Stanfield
Contributors
KEITH BARRETT-BEE (16,21), Bioscience 1 Moulescomb, Brighton, Sussex BN 4GJ,
Department, lCI Pharmaceuticals, United Kingdom
Mereside, Alderley Park, Macclesfield
SK10 4TG, United Kingdom JOSEPH DEVITO (4). Department of Micro
biology, University of Connecticut
RICHARD A. CALDERONE (20), Department Health Center, Farmington, CT 06030,
of Microbiology, Georgetown School of U.S.A.
Medicine, Washington, D.C. 20007,
U.S.A. GEORGE L. DRUSANO (2), Division oflnfec
tious Disease, University of Maryland
WARREN M. CASEY (15), Department of School ofM edicine, 10 S. Pine St., Balti
Microbiology, North Carolina State Uni more, MD 21201, U.S.A.
versity, Raleigh, NC 27695, U.S.A.
W. STEPHEN FARACI (8), Central Research
JOANNA CLANCY (II), Central Research Division. Pfizer Inc. , Groton, CT06340,
Division, Pfizer Inc., Groton, CT 06340, U.S.A.
U.S.A.
D. P. FIGGITT (14), DepartmentofPharma
JACK COLEMAN (10), Department of Bio ceutical Sciences, University of Notting
chemistry and Molecular Biology, Loui ham, Notthingham NG7 2RD, United
siana State University Medical Center, Kingdom
1901 Perdido St., New Orleans, LA
70112, U.S.A. MAKlKO FUKAYAMA (20), Department of
Microbiology, Georgetown University
EVA CZYZEWSKA (17), Department of School of Medicine. Washington, D.C.
Chemistry, Simon Fraser University, 20007, U.S.A.
Burnaby, B.C. V5A IS6, Canada
NAFSIKA H. GEORGOPAPADAKOU (9,18),
ASIS DAS (4), Department ofM icrobiology, Department of Chemotherapy (5812),
University ofC onnecticut Health Center, Roche Research Center, Nutley, NJ
Farmington, CT 06030, U.S.A. 07110-1199, U.S.A.
STEPHEN P. DENYER (14), Department of SARAH K. HIGHLANDER (12), Department
Pharmacy, Brighton Polytechnic. of Microbiology and Immunology, Bay-
viii I Contributors
lor College of Medicine, Houston, TX FRANCIS C. NEUHAUS (9), Department of
77030, U.S.A. Biochemistry, Molecular & Cell Biology,
Northwestern University, 2153 Sheridan
KUNIMOTO HOTTA (1), National Institute Road, Evanston, IL 60208, U.S.A.
of Health of Japan, Tokyo, Japan
A. CAMERON OEHLSCHLAGER (17), De
AKIRA IMADA (1), Biology Research Labo partment of Chemistry, Simon Fraser
ratories, Takeda Chemical Industries, University, Burnaby, B.C. V5A IS6,
Osaka, Japan Canada
SUZANNE JACKOWSKI (6), Department of LEO W. PARKS (15), Department of Micro
biology, North Carolina State Univer
Biochemistry, St. Jude Children's Re
sity, Raleigh, NC 27695, U.S.A.
search Hospital, 332 N. Lauderdale,
Memphis, TN 38105, U.S.A. CATHERINE P. REESE (II), Central Re
search Division, Pfizer Inc., Groton, CT
DAVID E. JACKSON (14), Department of 06340, U.S.A.
Pharmaceutical Sciences, University of
Noningham, Noningham NG7 2RD, NEIL S. RYDER (16), Sandoz F orschungins
titut, Gesellschaft M.B.H., Brunner
United Kingdom
Strasse 59, A1235 Wien, Austria
JOSEPH A. KOVACS (22), Critical Care JOHN F. RYLEY (21), ICI Pharmaceuticals,
Medicine Department, Clinical Center,
Mereside, Alderley Park, Macclesfield,
National Institutes of Health, Bethesda,
Cheshire SKIO 4TG, United Kingdom
MD 20892, U.S.A.
THOMAS SILHAVY (7), Department of Mo
GREGG Y. LIPSCHIK (22), Critical Care lecular Biology, Princeton University,
Medicine Department, Clinical Center, Princeton, NJ 08544-10/4, U.S.A.
National Institutes of Health, Bethesda,
JASON SPARKOWSKI (4), Department ofM i
MD 20892, U.S.A.
crobiology, University of Connecticut
Health Center, Farmington, CT 06030,
R. TODD LoRENZ (15), Department of Mi
U.S.A.
crobiology, North Carolina State Uni
versity, Raleigh, NC 27695, U.S.A. JAN S. TKAcz (19), DepartmentofFermen
tation Microbiology, Merck Sharp &
JOE LUTKENHAUS (5), Department of Mi Dohme Research Laboratories, P.O.
crobiology, Molecular Genetics & Im
Box 2000, Rahway, NJ 07065-0900,
munology, University ofK ansas Medical
U.S.A.
Center, 39th and Rainbow Blvd. , Kansas
City, KS 66103, U.S.A. THOMAS J. WALSH (13), Section of Infec
tious Diseases, National Cancer Insti
CHARLES S. McHENRY (3), Department of tute, Bldg. 10 Rm J3N-240, Bethesda,
Biochemistry, Biophysics and Genetics, MD 20892, U.S.A.
University of Colorada Medical School,
FREDERICK WARREN (4), Creative BioMo
4200 E. Ninth Ave., Denver, CO 80262,
lecules, Hopkinton, MA 01748, U.S.A.
U.S.A.
GEORGE M. WEINSTOCK (12), Department
RAIEEV MISRA (7), Department of Micro of Biochemistry and Molecular Biology,
biology, Arizona State University, University of Texas Medical School,
Tempe, AZ 85287-2701, U.S.A. Houston, TX 77225, U.S.A.
Contents
Preface xi
Antibacterial Chemotherapy
l. Historical Perspectives of Approaches to Antibiotics Discovery
Akira 11'f11Jda and Kunimoto Hotta
2. Bacterial Pathogens for the 1990s: A Case for New Drug Development 24
George L. Drusano
3. DNA Replication 37
Charles S. McHenry
4. RNA Synthesis in Bacteria: Mechanism and Regulation of Discrete 68
Biochemical Events at Initiation and Termination
Asis Das. Joseph DeVito. Jason Sparkowski.
and Frederick Warren
5. Bacterial Cell Division 117
Joe Lutkenhaus
6. Fatty Acid Biosynthesis 151
Suzanne Jackowski
7. Protein Secretion in Bacteria: A Chemotherapeutic Target? 163
Rajeev Misra and Thomas J. Silhavy
8. Cytosolic Enzymes in Peptidoglycan Biosynthesis as Potential 176
Antibacterial Targets
W. Stephen Faraci
9. Strategies in ~-Iactam Design 205
Francis C. Neuhaus and Nafsikn H. GeorgopapadlJkou
x I Contents
10. Lipid A Biosynthesis 274
Jack Coleman
11. Compromising the Protective Barrier of the Gram-Negative Bacterial 292
Cell Surface
Catherine P. Reese and Joanna Clancy
12. Bacterial Virulence Factors as Targets for Chemotherapy 323
Sarah K. Highlander and George M. Weinstock
Antifungal Chemotherapy
13. Invasive Fungal Infections: Problems and Challenges for Developing 349
New Antifungal Compounds
Thomas J. Walsh
14. Topoisomerase II Inhibitors: Prospects for New Antifungal Agents 374
David E. Jackson, D. P. Figgitt, and Stephen P. Denyer
15. Functions for Sterols in Yeast Membranes 393
Leo W. Parks, R. Todd Lorenz, and Warren M. Casey
16. Biochemical Aspects of Ergosterol Biosynthesis Inhibition 410
Keith Ba"ett-Bee and Neil Ryder
17. Rationally Designed Inhibitors of Sterol Biosynthesis 437
A. C. Oehlschlager and Eva Czyzewska
18. Chitin Synthase as a Chemotherapeutic Target 476
Nafsika H. Georgopapadakou
19. Glucan Biosynthesis in Fungi and its Inhibition 495
Jan S. Tkacz
20. Virulence-Associated Mannoproteins in Candida Albicans 524
Richard A. Calderone and Makiko Fukayama
21. Screening for Antifungal Activity 546
John F. Ryley and Keith Barrett-Bee
22. Chemotherapeutic Targets in Pneumocystis Carin;; 568
Gregg Y. Lipschik and Joseph A. Kovacs
Index 589
Preface
The prevalence of bacterial and fungal infections is reflected in the large market
share captured by antimicrobial agents (20% of the total pharmaceutical sales,
worldwide). Recent advances in medicine, such as transplantation and the use of
prosthetic devices, have resulted in an increased need for effective antiinfective
therapy. The treatment of chronic diseases (rheumatoid arthritis, diabetes,
asthma, cancer) and AIDS patients is often undermined by recalcitrant secondary
bacterial or fungal infections. Although many antibiotics are available to treat
bacterial infections, they are often less efficacious because of resistance develop
ment. For fungal infections, on the other hand, a wide array of treatment choices
is not currently available. New antimicrobial agents, with different structures and
mechanisms of action, are clearly desirable, as they are likely to be immune to
existing resistance mechanisms, and thus add to the armamentarium of the infec
tious disease physician.
The impetus for this collection of reviews was two· seminars that highlighted
potentially new antibacterial and antifungal targets. The seminars were organized
for and presented at the 1989 American Society for Microbiology meeting. Since
bacterial and fungal diseases represent some of the same challenges, we decided
to combine approaches for drug discovery in these two areas. The coverage of
novel targets is far from exhaustive; rather, only a selected number of worthwhile
approaches has been encompassed. By focusing basic biological concepts on
emerging chemotherapeutic targets, we hope that this volume will fill a gap
between general texts on antimicrobial drugs and highly specialized reference
books.
For many authors, writing a review in their area of expertise is not difficult to
contemplate, but our contributors were presented with a more difficult task-to
survey their areas from a chemotherapeutic perspective and to present their ideas
in a readable format for a multidisciplinary audience. In cases where biochemical
pathways are well defined, such as fatty acid or lipid A biosynthesis (chapters 6
and 10), specific enzymes that are unique to bacteria (acetoacetyl-ACP synthase)
xi
xii I Preface
or rate-limiting (UDP-GlcNac acyltransferase) were highlighted. In other cases,
where the biochemistry is less advanced, suggestions for specific targets were
made on the basis of genetic analysis. In still other cases, where specific targets
are yet to be defined, empirical approaches were discussed, such as the availability
of strains that allow screening methodology to be established.
The modern era of antimicrobial therapy began in the 1930s with the launch
of Prontosil, the first sulfonamide to be synthesized and developed as an antibacte
rial. Together with the successful development of penicillin as a systemic antibac
terial agent in the 1940s, it triggered an intensive search for new antimicrobials,
especially from fermentation sources. Early drug discoveries were largely the
result of serendipity; they produced substances (chloramphenicol, gentamicin,
polymyxin, tetracycline, amphotericin) with mechanisms of action that were
initially unknown. Our expanding knowledge and insight into how microbes
establish niches, survive, and grow have refined our approaches. Further, ad
vances in recombinant DNA technology have strengthened the ability to enrich
for drugs with specific modes of action. Yet despite our improved abilities in
discovering drugs, we are humbled by an older, more pervasive force-natural
selection. Selective pressure from antibiotic use has resulted in diminished po
tency and spectrum limitations in clinically useful antibiotics. Microbial resis
tance is the dark side, anthropocentrically speaking, of Darwinian evolution. A
historical perspective on the more recent approaches of antibiotic discovery is
given by Imada and Hotta (chapter 1).
Of antibacterials, ~-lactams continue to be the most successful class and
account for approximately two-thirds of the worldwide antibiotic market. An
update on recent developments and new insights for this drug class is provided
by Neuhaus and Georgopapadakou (chapter 9). Ergosterol synthesis inhibitors
are the most widely used antifungals (chapter 16) and drugs with this mechanism
of action are discussed by Barrett-Bee and Ryder.
Since the bacterial cell wall is a structure unique to procaryotes, the biosynthetic
enzymes for this giant macromolecule represent promising antibacterial targets.
Faraci (chapter 8) details the early steps in peptidoglycan synthesis, providing
background and rationale useful to the selection of a target enzyme.
The remarkable medical and commercial success of quinolones has rekindled
interest in nucleic acid synthesis and cell division. The identification of multiple,
unexploited targets in RNA and DNA synthesis is captured in reviews by Das et
al. (chapter 4) and McHenry (chapter 3), respectively. The roles of the many
players involved in bacterial cell division, with special consideration for the
essential role of FtsZ protein, are described by Lutkenhaus (chapter 5).
Some antibiotics are ineffective because they never reach targets within the
cell; drugs may be excluded from entry into the cell by cellular membranes or
effluxed by cellular pumps. Reese and Clancy (chapter 11) describe several
screening strategies designed to expand the spectrum and/or enhance the potency
of well-characterized antibiotics by disrupting the gram-negative cell envelope.