Ciba Foundation Symposium 186 - Antimicrobial Peptides

291 Pages·2016·9.35 MB·English

ANTIMICROBIAL
PEPTIDES
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Ciba Foundation Symposium 186
ANTIMICROBIAL
PEPTIDES
1994
JOHN WILEY & SONS
Chichester New York . Brisbane . Toronto . Singapore
OCiba Foundation 1994
Published in 1994 by John Wiley & Sons Ltd
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Suggested series entry for library catalogues:
Ciba Foundation Symposia
Ciba Foundation Symposium 186
vii+283 pages, 34 figures, 22 tables
Library of Congress Cataloging-in-Publication Data
Antimicrobial peptides1 [editors, Hans G. Boman, Joan Marsh, and
Jamie A. Goode].
p. cm.-(Ciba Foundation symposium ; 186)
“Symposium on Antimicrobial Peptides, held at the Ciba Foundation,
London, 18-20 January 1994.”
Includes bibliographical references and index.
ISBN 0 471 95025 4
1. Anti-infective agents-Congresses. 2. Protein drugs-
Congresses. 3. Peptides-Therapeutic use-Congresses.
4. Microbial peptides-Congresses. I. Boman, Hans G. 11. Marsh,
Joan. 111. Goode, Jamie. IV. Ciba Foundation. V. Symposium on
Antimicrobial Peptides (1994: Ciba Foundation)d) VI. Series.
RM409.A62 1994
61 5 ’ .3-d~20 94-2 1647
CIP
British Library Cataloguing in Publication Data
A catalogue record for this book is
available from the British Library
ISBN 0 471 95025 4
Phototypeset by Dobbie Typesetting Limited, Tavistock, Devon.
Printed and bound in Great Britain by Biddles Ltd, Guildford.
Contents
Symposium on Antimicrobial peptides, held at the Ciba Foundation,
London, 18-20 January 1994
Editors: Joan Marsh (Organizer) and Jamie A. Goode
This symposium is based on a proposal made by Hans G. Boman and
Joan Marsh
H. G. Boman Chairman’s opening remarks 1
R. B. Merrifield, E. L. Merrifield, P. Juvvadi, D. Andreu and H. G.
Boman Design and synthesis of antimicrobial peptides 5
Discussion 20
H. G. Sahl Gene-encoded antibiotics made in bacteria 27
Discussion 42
General discussion I Assaying antimicrobial activity 54
T. Ganz Biosynthesis of defensins and other antimicrobial peptides 62
Discussion 7 1
G. Kreil Antimicrobial peptides from amphibian skin: an overview 77
Discussion 85
B. P. A. Cammue, M. F. C. De Bolle, H. M. E. Schoofs, F. R. G. Terras,
K. Thevissen, R. W. Osborn, S. B. Rees and W. F. Broekaert
Gene-encoded antimicrobial peptides from plants 91
Discussion 101
D. Hultmark Drosophila as a model system for antibacterial peptides 107
Discussion 120
General discussion I1 Antimicrobial peptides from bees 135
V
vi Contents
P. J. Ham, C. Albuquerque, B. Smithies, R. Chalk, S. Klager and
H. Hagen Antibacterial peptides in insect vectors of tropical parasitic
disease 140
Discussion 151
S. Iwanaga, T. Muta, T. Shigenaga, N. Seki, K. Kawano, T. Katsu and
S.4. Kawabata Structure-function relationships of tachyplesins and
their analogues 160
Discussion 174
P. Elsbach Bactericidal permeability-increasing protein in host defence
aganist Gram-negative bacteria and endotoxin 176
Discussion 187
General discussion I11 Mechanism of membrane permeation by
cecropin B2 190
L. Jacob and M. Zasloff Potential therapeutic applications of magainins
and other antimicrobial agents of animal origin 197
Discussion 2 16
M. F. Flajnik Primitive vertebrate immunity: what is the evolutionary
derivation of molecules that define the adaptive immune system? 224
Discussion 233
J. E. Gabay Antimicrobial proteins with homology to serine
proteases 237
Discussion 247
C. L. Bevins Antimicrobial peptides as agents of mucosal immunity 250
Discussion 26 1
H. G. Boman Closing remarks 270
Index of contributors 273
Subject index 275
Participants
D. Andreu Department of Organic Chemistry, University of Barcelona,
Marti Franques 1-11 , E-08028 Barcelona, Spain
C. L. Bevins Division of Genetics and Molecular Biology, The Children’s
Hospital of Philadelphia, 34th Street and Civic Center Boulevard,
Philadelphia, PA 19104, USA
H. G. Boman (Chairman) Department of Microbiology, Stockholm
University, S-106 91 Stockholm, Sweden
P. Bulet Immune Response and Development in Insects, Institute for
Molecular and Cellular Biology, 15 Rue Rent Descartes, F67084
Strasbourg Cedex, France
B. P. A. Cammue F. A. Janssens Laboratory of Genetics, Catholic
University of Leuven, Willem de Croylaan 42, B-3001 Heverlee, Belgium
P. Casteels Insect Research Center, Lab0 Zoofysiologie, K L
Ledeganckstr. 35, B-9000 Gent, Belgium
P. Elsbach Department of Medicine, New York University Medical
Center, 550 First Avenue, New York, NY 10016, USA
M. K. Fagerhol Blood Bank and Department of Immunology, Ullevaal
Hospital, N-0407 Oslo, Norway
M. F. Flajnik Department of Microbiology and Immunology, University
of Miami, School of Medicine, PO Box 016960 (R138), Miami, FL
33101, USA
J. E. Gabay Department of Medicine, Division of Infectious Diseases,
Box 125, Cornell University Medical College, 1300 York Avenue,
New York, NY 10021, USA
vii
viii Participants
T. Ganz Department of Medicine, University of California at Los
Angeles, Room 37-055, Center for the Health Sciences, Los Angeles,
CA 90024, USA
E. Gazit (Ciba Foundation Bursar) Department of Membrane Research &
Biophysics, Weizmann Institute of Science, Rehovot 76100, Israel
P. J. Ham Centre for Applied Entomology and Parasitology, Department
of Biological Sciences, University of Keele, Near Newcastle-under-Lyme,
Staffordshire ST5 5BG, UK
J. N. Hansen Department of Chemistry and Biochemistry, University of
Maryland, College Park, MD 20742, USA
D. Hultmark Department of Molecular Biology, Stockholm University,
S-106 91 Stockholm, Sweden
S. Iwanaga Department of Biology, Kyushu University 33, Hakozaki,
Fukuoka 812, Japan
G. Kreil Institute of Molecular Biology, Austrian Academy of Sciences,
Billrothstrasse 11, A-5020 Salzburg, Austria
R. I. Lehrer Division of Hematology and Oncology, Department of
Medicine, Room 37-055, UCLA School of Medicine, Center for Health
Sciences, 10833 Le Conte Avenue, Los Angeles, CA 90024-1678, USA
R. B. Merrifield Department of Chemistry, The Rockefeller University,
New York, NY 10021, USA
S. Natori Faculty of Pharmaceutical Sciences, University of Tokyo,
Bunkyo-ku, Tokyo 113, Japan
J. E. Peel Animal Health Division Research, Ciba-Geigy, SA, CH-1566
Saint-Aubin FR, Switzerland
S. B. Rees Zeneca Agrochemicals, Jealott’s Hill Research Station,
Bracknell, Berkshire RG12 6EY, UK
H. G. Sahl Institut fur Medizinische Mikrobiologie und Immunologie der
Universitat Bonn, Sigmund Freund Strasse 25, D-53105, Germany
M. Zasloff Magainin Pharmaceuticals Inc, 5 11 0 Campus Drive, Plymouth
Meeting, PA 19462, USA
Novartis Foundation Symposium
Edited by Joan Marsh, Jamie A. Goode
Copyright 0 1994 by Ciba Foundation
Chairman’s opening remarks
Hans G. Boman
Department of Microbiology, Stockholm University, S- 106 91 Stockholm, Sweden
Where are the scientific roots of our present Ciba Foundation Symposium on
Antimicrobial peptides? In a general way the roots can be traced back a century
or more. They are to be found at the beginning of immunology (of mammals
and insects), in the discovery of phagocytosis, in the beginning of chemotherapy,
in the isolation of peptides from bee venom and from frog skins and in the
deliberate search for microbial antibiotics. The unifying goal in the medical part
of this early work was to find agents with a selective toxicity, what Ehrlich called
the ‘magic bullet’ of chemotherapy, an immune substance, a natural product
or a chemical that in a patient would effectively kill a harmful microbe without
unacceptable damage to the host.
Of course, penicillin also belongs to the roots of our present meeting:
after all, its nucleus is made from cysteine and D-valine. Fleming had discovered
lysozyme in 1922, the first bacteriolytic enzyme. His finding of penicillin
in 1929 was the result of following up a chance observation, but one might
say, in Pasteur’s words, that he did have a ‘prepared mind’. On the other hand,
the second phase of the penicillin saga, from 1939-1945, was a goal-oriented,
large-scale mission fuelled by the need to find an effective treatment
for infected wounds from World War 11. These efforts included some 40
laboratories on both sides of the Atlantic which produced about 1200
confidential reports on the structure of penicillin, its synthesis and production
by fermentation.
In a more direct way, the history of antibacterial peptides runs in parallel
with the penicillin work. It starts in 1939 with Dubos’ demonstration that ‘an
unidentified soil bacillus’ produced some antibacterial compounds that could
prevent pneumococcal infections in mice. The year after, Hotchkiss and Dubos
reported a partial purification of the bactericidal substances produced by this
soil bacterium, now identified as Bacillus brevis. Then, in 1941-1942, they
described how, starting from a B. brevis culture, they had purified and
crystallized tyrocidine and gramicidin and shown them to be composed of amino
acids, some of them D-amino acids. Both these antibacterial peptides turned
out to be more or less toxic; tyrocidine to the extent that it could never be used
to treat an infection. However, before penicillin became available, gramicidin
was to a limited extent used as a therapeutic agent.
1
2 Boman
In another way, gramicidin was also a forerunner to cecropins, defensins and
magainins because it was the first peptide antibiotic found to induce the
formation of voltage-gated anion channels in artificial membranes. As we all
know, this is a property of several of the peptides to be discussed at this meeting,
although it is still not clear if this is the primary mechanism by which bacteria
are killed. However, there is a fundamental difference between the forerunners
and the antimicrobial peptides to be discussed here: all antimicrobial peptides
have their own genes. On the other hand squalamine, a recently discovered shark
antibiotic, is a steroid and, as such, it cannot be made from an RNA template,
but must be made stepwise just as was also found for tyrocidine and gramicidin.
Other forerunners of today’s antibacterial peptides were, in the 1960s, the
bee venom toxin, melittin, and the frog skin peptide, bombinin. From an early
stage, these two peptides were claimed to be antibacterial, although this seems
mainly to have been stated and as far as I know only once really documented
for bombinin. However, bombinin at that time was most likely a mixture of
peptides and the mixture was, like melittin, quite haemolytic. Thus, even if their
action on membranes may have been similar to that of cecropins and magainins,
bombinin and melittin did not show the same membrane specificity. Today
melittin is still a toxin, but one melittin domain has been used together with
a cecropin domain for the design of novel antibacterial, non-haemolytic peptides.
Bombinin is now separated into a family of closely related peptides. Some of
these are antibacterial and non-haemolytic, others are both antibacterial and
haemolytic and they also contain a D-amino acid.
The organized search for antibiotics, which started towards the end of World
War 11, has now produced so many antibiotics that nobody seems to know how
many there are. The number of antibiotics described in scientific journals and/or
patented may be as high as 20 OOO, although only a few hundred of these may
be in use in daily therapy. The widespread clinical use of antibiotics (and their
misuse in the production of animals) has led to the spread of plasmid-borne
resistance genes that are posing an increasing threat to the future medical use
of these agents. The development of this phenomenon was the subject of a Ciba
Foundation Symposium on drug resistance in 1957 and on penicillin resistance
in 1962. However, both of these meetings seem to have been too early to consider
infectious, plasmid-borne drug resistance. Up to now there has only been one
more Ciba Foundation Symposium related to antibiotics and this was quite
recently. In 1992, the Foundation arranged a meeting on secondary
metabolites-a term used mainly for attempts to understand the biosynthesis
and the production of microbial antibiotics. Thus, in a way, today’s conference
is the first Ciba Foundation Symposium focused directly on a new type of
antibiotic, in this case gene-mediated and produced by animals, plants or
microbes. For animals, these antibacterial peptides serve as immune substances
and they are primary defence agents of innate immunity rather than secondary
metabolites. Their potential use as drugs is motivated in part by the increasing