Target sites of fungicide action

339 Pages·1992·32.6 MB·English

by  Köller

Target Sites
of
Fungicide Action
Editor
Wolfram Koller
Assistant Professor
Department of Plant Pathology
Cornell University
New York State Agricultural Experiment Station
Geneva, New York
Boca Raton London New York
CRC Press
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BocTaay lRor a&t Fornan ciAs Gnronu pA, anr bionfro rmLao bnudsinoenss
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Library of Congress Cataloging-in-Publication Data
Target sites of fungicide action/editor, Wolfram D. Köller,
p. cm.
Includes bibliographical references and index.
ISBN 0-8493-6855-3
1. Phytopathogenic fungi--Control. 2. Fungicides--Physiological
effect. 3. Phytopathogenic fungi--Physiology. I. Koller, Wolfram D.
SB733.T37 1991
632’ .952--dc20 91-22650
A Library of Congress record exists under LC control number: 91022650
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PREFACE
Fungi are not only the most important class of plant pathogenic organisms, but they are
also the causal agents of animal and human mycoses. Fungal diseases of crops can be
devastating, and disease symptoms have been described since farming became the major
source of our food and fiber supply. 1 Although the incidence of human diseases caused by
fungi is less than that of bacterial and viral infections, they do occur and can be life-
threatening.2 Major weapons in the combat of fungal diseases have been, in both cases,
chemicals with antifungal activities. Interestingly, two different names have emerged in the
past. The term "fungicide" describes antifungal compounds developed for agriculture,
whereas "antifungal agent", "antifungal drug" and "antimycotic" are more commonly
used in medicine. From a historic point of view, this distinction is not surprising. The first
generation of agricultural fungicides had no application in medicine, and the first antifungal
drugs introduced in the late 1950s, amphotericin B and 5-fluorocytosine, were useless for
farmers. Over the last two decades, however, the distinction between the two classes of
antifungal compounds has become less pronounced. In particular the discovery and devel-
opment of azoles with their broad field of application in agriculture and medicine has triggered
increasing cooperation between the mycological disciplines concerned with either control of
plant diseases or antifungal chemotherapy. While the recognition of mutual scientific interests
was on the rise, the future perspectives for fungicides and antifungal drugs began to drift
apart. Although the common goal remained the same, agricultural fungicides and medical
drugs are viewed differently. What has happened?
It had been the progress in chemistry and chemical engineering in the first half of the
20th century that made the reliable control of insects, weeds and plant diseases a reality.
The initial acceptance of early organic pesticides was overwhelming, and it is worth re-
membering that P. Muller, the inventor of DDT, was honored with the Nobel Prize in 1948.
This positive perception has vanished and given place to a global awareness of pesticide
threats to our environment. Undoubtedly, the chemical control of plant diseases, although
still irreplaceable, has become part of our current "chemophobia". The issue has become
increasingly emotional, and public concerns are not always justified from a scientific point
of view. Moreover, the tremendous progress in safety and application rates made over the
last four decades is not always fully recognized and appreciated. Regardless of many existing
misperceptions, however, some of the fungicide-related problems are real, and scientists
engaged in fungicide research will have to answer a question of considerable importance:
Was the development of chemical fungicides a dead-end street with low expectations for
the future, or will it be feasible to apply our scientific progress to the development of novel
and effective chemical control agents with extremely specific targets and thus without side
effects on non-target organisms and the environment?
Many scientists at the forefront of plant disease control appear to have answered this
question. They have dismissed chemical measures from their arsenal of future strategies,
and the term "innovative" has become a synonym for "non-chemical". For example, future
prospects for chemical control are no longer part of a recent book on innovative approaches
to plant disease control. 3 Expectations are high of finding widespread and durable solutions
by recombinant DNA technology, be it through the engineering of disease-resistant crop
cultivars, or through the construction of greatly improved biocontrol agents. Undoubtedly,
the exciting potential of biotechnology will have beneficial impact in the future. But will it
make chemical control entirely obsolete, and will it always lead to entirely "nontoxic"
means of plant disease control? Zehf'l concluded in his recent reflections on innovation in
plant disease control: "We might even find that new chemical pesticides carefully regulated
by government agencies and applied by informed users may be among the safest of the
mechanisms available to control many plant diseases and pests." It certainly would be
unwise to abandon innovative research on novel fungicides before safe and lasting ''non-
chemical" alternatives are in sight. Most likely, the breeding of disease-resistant cultivars,
the development of biocontrol agents, and new chemical fungicides will co-exist in the future
as they have in the past.
In contrast to chemical fungicides, the public demand for novel antifungal drugs has
increased over the last decade. The incidence of fungal infections is on the rise since an
increasing number of immunocompromised patients became prone to opportunistic and
sometimes life-threatening fungal infections. 56 The treatment of deep-seated and systemic
•
mycoses is difficult with the currently prescribed arsenal of antimycotic drugs, and a number
of new antimycotics are under clinical development. 7 Mandatory for the treatment of many
opportunistic fungal infections is the availability of highly specific antifungal drugs without
side effects on the patient. Progress toward high levels of fungal specificity has already been
made with the group of systemic fungicides developed for agriculture, and newer devel-
opmental antifungal drugs are becoming increasingly similar to these site-specific fungicides,
in particular within the group of sterol biosynthesis inhibitors.
In general, the systemic treatment of any patient, be it plant, animal or human, is only
possible with inhibitors of fungal-specific targets. Specificity, however, also has its short-
comings. As the experience with specific agricultural fungicides has shown, these inhibitors
are more prone to the development of resistance. Although fungal resistance has not been
a serious problem for the current antimycotics, this might change if immunocompromised
patients with mycotic diseases have to be maintained under long-term treatment. The iden-
tification of suitable and novel antifungal targets, the modification of already existing in-
hibitors, and the prediction of inherent risks of resistance will require profound data on the
molecular mode of inhibitor action. The contributions in this book are a comprehensive
summary of our current knowledge, but they are also meant to raise questions and to stimulate
future research.
The first two chapters are dedicated to the carboxamides and hydroxypyrimidines. They
represent groups of relatively old systemic fungicides with a remarkable level of specificity
and selectivity. The benzimidazoles described in Chapter 3 with their broad spectrum of
plant disease control have been severely affected by the development of resistance. The
more recent cloning and sequencing of the target gene has not only provided insight into
the molecular specifics of resistance, but it also explained the mode of action of compounds
with exclusive activity against resistant genotypes. Edlich and Lyr (Chapter 4) describe the
mode of action concepts that emerged only recently for a group of rather unrelated fungicides,
the dicarboximides and the aromatic hydrocarbons. The class of specific fungicides available
for the control of oomycetes is described in depth in Chapter 5. All antifungal inhibitors
covered in the first five chapters are exclusively used in agriculture. This restriction is not
always apparent from a mode of action point of view, and the better understanding of
molecular principles might lead to closely related inhibitors with activities against a broader
or different spectrum of fungal pathogens. The melanin biosynthesis inhibitors (Chapter 6)
are different from all other antifungal agents and represent a novel and desirable trait in
fungal disease control. They are neither fungitoxic nor fungistatic but interfere with the
penetration of fungal pathogens into their plant hosts and, thus, are the first representatives
with an indirect mode of action. The inhibitors of fungal sterol biosynthesis described in
Chapters 7, 8 and 9 comprise the currently most successful group of antifungal compounds.
Several different enzymes of the sterol biosynthetic pathway are already antifungal targets,
and interesting inhibitor lead structures for additional enzymes are promising. Moreover,
the sterol biosynthesis inhibitors have crossed the border of disciplines and are successfully
used in both agriculture and medicine. Several specific fungicides with known modes of
action did not warrant a separate chapter. They are described, however, in Chapter 10,
which is dedicated to the role of molecular studies in fungicide research. Finally, the question
is asked in Chapter 11 whether it might become feasible to use industrial enzymes as disease
control agents.
The contributions as a whole are a mirror of the tremendous progress made over the
last two decades. This progress becomes immediately evident from the contents of a mon-
ograph dedicated to the same subject, written by Lukens in 1971.8 There are no reasons to
believe that progress will slow down in the future. Hopefully, this book will stimulate ideas
and encourage research in the field of antifungal inhibitors.
Wolfram Koller
Geneva, New York
I. Agrios, G. N., Plant Pathology, 3rd ed., Academic Press, San Diego, 1988.
2. Rippon, J. R., Medical Mycology, 2nd ed., W. B. Saunders, Philadelphia, 1982.
3. Chet, 1., Innovative Approaches to Plant Disease Control, John Wiley, New York, 1987.
4. Zehr, E. 1., Reflections on innovation in plant disease control, Plant Dis., 73, 372, 1989.
5. Bodey, G. P., Fungal infections in cancer patients, Ann. N.Y. Acad. Sci., 544, 431, 1988.
6. Spencer, P. M. and Jackson, G. G., Fungal and mycobacterial infections in patients infected with the
human immunodeficiency virus, J. Antimicr. Chemother., 23 (Suppl. A), 107, 1989.
7. Saksena, A. K., Girijavallabhan, V. M., Cooper, A. B., and Loebenberg, D., Recent advances in
antifungal agents, Annu. Rep. Med. Chern., 24, Ill, 1989.
8. Lukens, R. J., Chemistry of Fungicidal Action, Springer-Verlag, New York, 1971.
EDITOR
Wolfram Koller is assistant professor of plant pathology at the Geneva Campus of
Cornell University, where he joined the faculty in 1986. He was trained in chemistry and
biochemistry and received his Ph.D. in chemistry from the Philipps University of Marburg
in 1979. He spent two postdoctoral years as a recipient of a DFG fellowship at the Institute
of Biological Chemistry of Washington State University in Pullman. Thereafter he became
the head of a biochemistry laboratory in fungicide research at Bayer in Leverkusen.
His research interest is focused on the biochemistry of plant disease control. He has
authored more than 60 scientific contributions and is co-author of a textbook on undergraduate
chemistry training. He has given more than 30 invited lectures and seminars. His current
appointments are on the editorial board of Phytopathology and on several national and
international committees in pesticide resistance.
CONTRIBUTORS
Pierre Benveniste, D.S. Hideo Ishii, M.Agr.
Professor Laboratory Head
Institut de Biologie Moleculaire des Division of Plant Protection
Plantes Fruit Tree Research Station, MAFF
Institut de Botanique Tsukuba, lbaraki, Japan
Universite Louis Pasteur
Strasbourg, France Paul A. J, Janssen, Dr.
President and Director of Research
Amanda Davis, B.Ag.Sci. Janssen Pharmaceutica
Research Scholar Beerse, Belgium
Department of Biochemistry
University of Melbourne Wolfram Koller, Ph.D.
Parkville, Victoria, Australia Assistant Professor
Cornell University
Wilfried Edlich, Dr. Department of Plant Pathology
Research Scientist New York State Agricultural Experiment
Insitute of Plant Protection Research Station
Kleinmachnow Geneva, New York
Kleinmachnow, Germany
Yasuyuki Kubo, Ph.D.
Assistant Professor
S. G. Georgopoulos, Ph.D.
Laboratory of Plant Pathology
Professor
Faculty of Agriculture
Department of Plant Pathology
Kyoto University
Agricultural University of Athens
Kyoto, Japan
Athens, Greece
Horst Lyr, Dr.
Bruce Grant, Ph.D.
Professor and Department Director
Reader in Biochemistry
Institute of Plant Protection Research
Department of Biochemistry
Kleinmachnow
University of Melbourne
Kleinmachnow, Germany
Parkville, Victoria, Australia
A. J. Poulose, Ph.D.
Julia M. Griffith, Ph.D. Research Director
Research Fellow Exploratory Research
Department of Biochemistry Genencor International
University of Melbourne South San Francisco, California
Parkville, Victoria, Australia
Alain Rahier, D.S.
D. W. Hollomon, Dr. Directeur de Recherche
Department of Agricultural Sciences Centre National de la Recherche
University of Bristol Scientifique
AFRC Institute of Arable Crops Research lnstitut de Biologie Moleculaire des
Long Ashton Research Station Plantes
Bristol, United Kingdom Strasbourg, France
Hugo Vanden Bossche lsamu Yamaguchi, Ph.D.
Department Head Senior Scientist and Professor
Department of Comparative Biochemistry Microbial Toxicology Laboratory
Janssen Research Foundation The Institute of Physical and Chemical
Beerse, Belgium Research (RIKEN)
Wako-shi, Saitama, Japan
G. A. White, Ph.D.
Research Scientist
Agriculture Canada
Research Centre
London, Ontario, Canada
TABLE OF CONTENTS
Chapter 1
Target Sites of Carboxamides ............................................................ 1
G. A. White and S. G. Georgopoulos
Chapter 2
Target Sites of Hydroxypyrimidine Fungicides .......................................... 31
D. W. Hollomon
Chapter 3
Target Sites of Tubulin-Binding Fungicides ............................................. 43
Hideo Ishii
Chapter 4
Target Sites of Fungicides with Primary Effects on Lipid Peroxidation ................. 53
W. Edlich and H. Lyr
Chapter 5
Target Sites of Fungicides to Control Oomycetes ....................................... 69
J. M. Griffith, A. J. Davis, and B. R. Grant
Chapter 6
Target Sites of Melanin Biosynthesis Inhibitors ........................................ 101
Isamu Yamaguchi and Yasuyuki Kobo
Chapter 7
Antifungal Agents with Target Sites in Sterol Functions and Biosynthesis ............. 119
Wolfram Koller
Chapter 8
Target Sites of Sterol Biosynthesis Inhibitors in Plants ................................. 207
P. Benveniste and A. Rahier
Chapter 9
Target Sites of Sterol Biosynthesis Inhibitors: Secondary Activities on Cytochrome
P-450-Dependent Reactions ............................................................ 227
Hugo Vanden Bossche and Paul A. J. Janssen
Chapter 10
Target Research in the Discovery and Development of Antifungal Inhibitors .......... 255
Wolfram Koller
Chapter 11
Biotechnology and Fungal Control ..................................................... 311
A. J. Poulose
Index ................................................................................... 319