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© 2008 Plant Management Network.
Accepted for publication 18 December 2007. Published 18 April 2008.


Milestones in Fungicide Discovery: Chemistry that Changed Agriculture


Carla J. Klittich, Research and Development, Discovery Biology, Dow AgroSciences LLC, 9330 Zionsville Road, Indianapolis, IN 46268


Corresponding author: Carla J. Klittich. cklittich@dow.com


Klittich, C. J. 2008. Milestones in fungicide discovery: Chemistry that changed agriculture. Online. Plant Health Progress doi:10.1094/PHP-2008-0418-01-RV.


Abstract

Fungicides have repeatedly altered the way crops are grown and farmers’ expectations of crop health. This review focuses on the inventions that were turning points in agriculture and the evolution in our expectations of fungicides.


Introduction

Farmers have been at the mercy of plant diseases since plants were first domesticated. The mysterious appearance of blights and mildews, apparently coming from nowhere, led to theories of gods, vapors, demons, and decay as causes of disease. Beginning in the early 1800s, plant scientists and chemists began the long journey to discover and invent fungicides that would reduce disease losses. Many discoveries were made, and this review summarizes the exceptional few that irrevocably changed agriculture (summarized in Table 1).


Table 1. Milestone fungicides (25).

Common name Trade name (example)x  Class of chemistry Year of launch Mode of action WHO toxicity classy 
Copper sulfate   Inorganic 1873 General toxicant II
Chloro (2-hydroxy phenyl) mercury UPSULAM Organo-
mercurial
1913 General toxicant       
Thiram   Dithio-
carbamate
1940 General toxicant III
Ferbam   Dithio-
carbamate
1943 General toxicant U
Mancozeb DITHANE™ Dithio-
carbamate
1961 General toxicant U
Carboxin VITAVAX Carboxamide 1969 Mitochondrial electron transport Complex II U
Benomyl BENLATE Benzimidazole 1970 β-tubulin synthesis U
Triadimefon BAYLETON Triazole 1976 Ergosterol biosynthesis III
Metalaxyl RIDOMIL, APRON Phenylamide 1977 RNA transferase III
Fosetyl-Aluminum ALIETTE Phosphonate 1977 Not conclusively determined U
Azoxystrobin QUADRIS, AMISTAR, HERITAGE Strobilurin 1996 Mitochondrial electron transport Complex III U
Tricyclazole BEAM™ Benzothiazole 1976 Melanin biosynthesis inhibitor II
Probenazole ORYZEMATE Benzisothiazole 1979 Systemic acquired resistance U
Acibenzolar-S-methyl BION, ACTIGARD Benzo-
thiadiazole
1996 Systemic acquired resistance III

 

Quinoxyfen FORTRESS™

QUINTEC™

Quinoline 1997 Signal transduction U

 x DITHANE™, BEAM™, FORTRESS™, and QUINTEC™ are trademarks of Dow AgroSciences LLC.

 y World Heath Organization classification for estimating acute toxicity of pesticides (25): II = Moderately hazardous; III = Slightly hazardous; and U = Product unlikely to present acute hazard in normal use.


1807 – The First Fungicide

B. Prévost discovered the first chemical means for controlling disease in a practical way in 1807. Bunts and smuts of cereals had been a key limitation to cereal cultivation for centuries, appearing unexpectedly on healthy-looking plants that should have been producing grain. Prévost was the first to observe that spores, which grew into tiny germinating "plants," caused wheat bunt. He then made the serendipitous observation that a weak copper solution (generated when he held the spore suspension in a copper vessel) prevented their growth. Through experimentation, he demonstrated that farmers could control bunt by wetting wheat kernels with a copper sulfate solution. Previous methods of bunt control required steeping the seeds in salt water and lime or putrefied urine, which were not very effective (18). Copper-based seed treatments remained popular in some countries, including France, through the end of the 20th century.


1885 – The First Foliar Fungicide

Eight decades passed before a method of controlling foliar disease was discovered; in 1885, P. M. A. Millardet described the effective use of a mixture of copper sulfate and lime for control of downy mildew on grapevines. A farmer in the Bordeaux region of France had mixed the unattractive concoction to discourage university students from pilfering grapes on their way to class, and Millardet noticed that the sprayed vines retained their leaves while unsprayed plants had been defoliated by downy mildew (1). This unexpected discovery, thereafter known as Bordeaux mixture, stimulated research into other possible methods of controlling fungal diseases, a search that gained momentum during the 20th century. To this day, copper-based foliar fungicides are used to control a variety of fungal diseases, particularly on fruits and vegetables, and for suppression of bacterial diseases. Many have new-found utility as disease control agents in organic food production.


1915 – Broad-Spectrum Control of Seed-Borne Disease

The first organic (carbon-based) fungicides synthesized in a laboratory were the organomercurial seed treatments. Even though copper seed treatments had been used on cereals for 100 years, they controlled only bunt and could be phytotoxic. Early in the 20th century, discoveries made by fledgling pharmaceutical companies studying the medicinal aspects of compounds made from metals and dyestuff intermediates stimulated plant pathologists to look for compounds that could control plant diseases. The first organomercurial seed treatment, chloro (2-hydroxyphenyl) mercury, was introduced in Germany in 1913 (19). Research on organomercurials continued through the 1920s and 1930s, leading to commercialization of the 2-methoxyethyl silicate and acetate salts of 2-hydroxyphenyl mercury, among others. These seed treatments were a breakthrough for cereal farmers because the treatments had good seed safety and controlled mycelia of seed-borne fungi such as Fusarium and Dreschlera as well as bunt. They also provided protection against soil-borne Fusarium species, resulting in improved stand establishment (14), and their vapor activity helped overcome incomplete coverage of the seed surface (26). The treatments were so effective and inexpensive that cereal seed treatment became routine.

The organomercurial seed treatments had some flaws. They were not deeply systemic, so loose smuts were not controlled. Despite their multi-site mode-of-action and use only once per year, resistance eventually developed in some populations of Dreschlera on barley and oats. Environmental toxicity and the persistence of mercury led most countries to ban the organomercurials when safer alternatives became available, although not without considerable protest from farmers. Despite the availability of alternative treatments, organomercurial seed treatments were not banned in the UK until 1992 (14).


1940 – The First Broad-Spectrum Protectant Fungicides

The early success of organomercurials was followed two decades later by the discovery of organic compounds complexed with metals that could control foliar diseases of plants. Control of foliar disease in the early 20th century was limited to inorganic mixtures of lime and copper salts. These mixtures controlled only a handful of diseases and were often phytotoxic. The discovery of the dithiocarbamate fungicides was a tremendous breakthrough. The first patent for this chemistry was issued in 1934 to Tisdale and Williams, but dithiocarbamate fungicides were not commercialized until 1940, when thiram was described as an effective seed treatment, and 1943, when ferbam was described as a foliar fungicide (1,19). The technology advanced with the introduction of the ethylenebis (dithiocarbamates), including nabam, zineb, and maneb (19), and peaked with the development of mancozeb by Rohm and Haas in 1961. For the first time, farmers had fungicides that effectively controlled devastating diseases such as potato late blight and leaf spots caused by fungi such as Venturia, Alternaria, and Septoria (14). Because of their spectrum, these fungicides provided the greatest benefit for fruit and vegetable growers. The dithiocarbamate compounds had the advantage of low toxicity to mammals, plants, and the environment, and with their multi-site mode-of-action they remain a critical component of resistance management for newer fungicides. The value of these fungicides is demonstrated by the fact that mancozeb is still the largest selling fungicide in the world.

Despite the success of the dithiocarbamate fungicides, there remained many diseases that they did not control. They were not very effective against important diseases such as powdery mildews and rusts, and their strictly protectant nature required frequent applications that had to be made prior to infection. Application rates were high and good spray coverage was essential since there was no redistribution within the plant. Systemic organophosphate insecticides (such as dimethoate) had been commercialized since the 1950s, and farmers were well aware of the benefits of systemic pest control (7). The invention of a systemic fungicide would be a true breakthrough for plant disease control.


1969 – The First Systemic Seed Treatment

The first systemic fungicide was a milestone both because it had true redistribution in the plant and because it had the potential to replace organomercurial cereal seed treatments. Carboxin, described in 1966 and commercialized in 1969, not only controlled surface-borne bunts and smuts but also penetrated deeply into the seed embryo, where it eradicated loose smut infections. Carboxin also gave excellent control of early season rust and Rhizoctonia damping off, although it was less effective on seed-borne Fusarium and Dreschlera diseases than organomercurials (18). Additionally, carboxin had good plant safety as a seed treatment of row crops, particularly cotton and canola. Resistance development has been slow, although field resistance was eventually documented in some populations of Ustilago nuda after many years of continuous use (16). Despite their excellent fit in limited markets, the utility of carboxin and its derivative for foliar applications, oxycarboxin, was never broad because of their specificity for Basidiomycetous diseases.


1970 - The First Broad-Spectrum Foliar Systemic Fungicide

The first fungicide with the broader spectrum typical of dithiocarbamates and the systemic activity of organophosphate insecticides was benomyl. This benzimidazole fungicide was launched by DuPont in 1970 and provided systemic and curative activity at low rates, with excellent plant and mammalian safety. For the first time, farmers were able to cure existing infections, extend intervals between sprays, and not worry about perfect coverage. These characteristics made benomyl extremely popular from its introduction (23). The list of fungi controlled by benomyl and other benzimidazole fungicides is extensive. Most Ascomycetes with light-colored spores are controlled, including numerous types of leaf spots, fruit rots caused by Botrytis and Penicillium, powdery mildews, and stem diseases such as eyespot. Some Basidiomycetes, such as selected anastamosis groups of Rhizoctonia solani, are controlled, but most are not. Diseases caused by Oomycetes and by Ascomycetes with dark spores (such as Alternaria and Helminthosporium) are also not controlled (4). Additional benzimidazole fungicides launched after the introduction of benomyl include thiophanate-methyl (1971) and carbendazim (1974).

The characteristics that made benomyl so popular and effective also had a troubling aspect. Repeated, exclusive use on polycyclic diseases led to rapid development of resistant fungal populations. Within three years of introduction, resistance was reported in field and/or greenhouse populations of Erysiphe, Botrytis, Penicillium, and Cercospora (23). Benomyl’s single-site mode-of-action could be bypassed by the fungus with a single mutation. Resistant strains could be equal in fitness to their susceptible counterparts, resulting in persistence of some resistant populations even when the benzimidazole fungicides were discontinued (5). The agrichemical industry learned an important lesson about fungicides with specific modes-of-action from the benzimidazole experience, and now begins assessment of resistance risk early in fungicide development so that resistance management plans are in place at product launch (5).

The benzimidazole fungicides were very successful on fruits and vegetables but had less utility for cereal diseases, since they gave no control of rusts or Dreschlera species. Further, the cereal diseases that were controlled, in particular the powdery mildews, rapidly became resistant (23). A systemic, broad-spectrum fungicide with a new mode-of-action was still needed for foliar disease control in cereals.


1976 – A Systemic, Curative Foliar Fungicide for Cereals

The breakthrough for cereal disease management came in 1976 with the introduction of the triazole fungicide triadimefon by Bayer (15). Triadimefon provided curative as well as protectant activity, low application rates, and excellent redistribution in the plant. The spectrum of control covered all major cereal diseases and included most Ascomycetes and Basidiomycetes (but not Oomycetes). Additional triazole fungicides were introduced over the next two decades with improved potency and plant safety on cereals (e.g., epoxiconazole), a broader effective spectrum (e.g., propiconazole, tebuconazole), or specialized applications (e.g., difenoconazole and triticonazole for seed treatment) (15). The triazole fungicides significantly increased farmers’ expectations for fungicides, particularly for reach-back (curative) activity and redistribution to unsprayed growth.

The revolutionary triazoles have not been immune to challenges in their development and maintenance. They have well-documented side effects on plants. Application to shoots and roots often reduces elongation and causes leaves to be smaller, thicker, and greener. Treated plants may be delayed in senescence, which can impede harvest or improve yields, depending on the crop (3). A larger concern has been resistance development, since the triazoles have many of the same properties as the benzimidazoles (curative activity, single-site MOA, multiple applications per season). Resistance to the triazole fungicides (and other inhibitors of C14-demethylase in ergosterol biosynthesis) developed first in the powdery mildews and has been observed (but is less problematic) on other diseases (15). Unlike resistance to the benzimidazoles, resistance to the triazoles involves multiple genes with intermediate levels of resistance and incomplete cross-resistance between different fungicides (15). The use of mixtures has been remarkably successful in maintaining useful activity against most fungal targets for three decades.

The launches of benzimidazole and triazole fungicides provided potent, systemic fungicide solutions for Ascomycete and Basidiomycete diseases, but control of devastating Oomycete diseases such as potato late blight and grape downy mildew was limited to frequent sprays of protectant fungicides. Root rots of established plants (caused by Phytophthora and Pythium) and systemic downy mildews could not be controlled at all, and took an unknown toll on crop yield.


1977 – The First Systemic Oomycete Fungicides

The launch of the phenylamide fungicide metalaxyl in 1977 by Ciba-Geigy changed farmers’ expectations for control of Oomycete diseases (20). This fungicide was an immediate success because of its outstanding properties: high potency; excellent curative and protectant activity; excellent redistribution and protection of new growth; control of all members of the order Peronosporales (including Pythium); and flexible application methods including foliar spray, seed treatment, and root drench (21). As with the benzimidazoles, the phenomenal success and overuse of the phenylamide fungicides led to rapid resistance development. Significant resistance to metalaxyl was first described in 1980 on cucumber downy mildew and late blight (20). Resistance developed more rapidly where metalaxyl was used alone, disease pressure was very high, and applications were made curatively. Ciba-Geigy responded with the development of fungicide prepacks containing metalaxyl and protectant fungicides, such as mancozeb, which extended the product life significantly (20,21). The phenylamide experience was pivotal in the formation of the Fungicide Resistance Action Committee (FRAC), which developed a coordinated strategy across rival companies to limit the number of recommended phenylamide applications per season (21). Despite a coordinated effort, susceptibility to phenylamides gradually eroded in populations of many foliar pathogens, and foliar uses of metalaxyl are now met by other fungicides in many markets. Soil and seed applications of metalaxyl (or its active enantiomer, mefenoxam) have generally retained their effectiveness, particularly for control of Pythium and the root-infecting species of Phytophthora.

A second type of oomycete fungicide was launched the same year as metalaxyl; fosetyl-aluminum, invented by Rhone-Poulenc, also controls oomycete diseases, but has a more limited spectrum than metalaxyl (21). It has the unusual characteristic (for a fungicide) of phloem as well as xylem mobility (21), controlling soil-borne diseases such as Phytophthora root rot of citrus with applications to the trunk or foliage. Activity of fosetyl-aluminum has been durable in the field despite regular use over many years (8,21); its mode of action (direct activity on fungal growth, stimulation of host defense response, or a combination of these) is still equivocal (8,11).

By the mid-1980s, resistance was developing in some fungi to the triazole and phenylamide fungicides, providing an opportunity for introduction of new broad-spectrum fungicides with a different mode-of-action.


1996 – Broad-Spectrum Fungicides with Novel Spectrum and New Mode-of-Action

The natural products strobilurin A and oudemansin had been isolated from a saprophytic fungus in the late 1970s and demonstrated excellent broad-spectrum control of fungal growth. Parallel research programs at ICI and BASF in the early 1980s were focused on invention of synthetic analogs with improved UV stability and spectrum (27). These strobilurins differed from previous fungicides in combining an unusually broad spectrum (including control of Oomycetes, Ascomycetes, and Basidiomycetes) with a site-specific mode-of-action. The first strobilurin products were launched in 1996; kresoxim-methyl from BASF had strong utility on cereals, and azoxystrobin from Zeneca was suitable for a variety of crops due to its plant safety and strong redistribution. Additional strobilurins, including trifloxystrobin, picoxystrobin, and pyraclostrobin, have been launched by a number of companies. These compounds became popular in many markets because of their versatility at controlling diseases from different taxonomic classes, such as powdery and downy mildew on vines, and sheath blight and blast on rice (9). An additional benefit came from the physiological response of the plant to the fungicide; as with the triazoles, strobilurins often enhanced plant greening and delayed senescence, leading to improved yields even in the absence of significant disease pressure (2,9). Some of the strobilurin fungicides commercialized after azoxystrobin were tailored to the cereal market rather than the vegetable and fruit market, with attributes of long residual protection, vapor phase activity, and moderate redistribution. Widespread use of strobilurins has already led to the development of resistance for several diseases, including wheat, barley, and cucumber powdery mildew, grape and cucumber downy mildew, apple scab, black sigatoka on bananas (2), and Septoria blotch on wheat (17). Resistance is typically caused by single base pair mutations in the mitochondrial gene encoding cytochrome b (2). Current recommendations for use of strobilurin fungicides limit the number of applications per season, suggest alternation of application with fungicides that have different modes-of-action, and recommend mixtures for many markets (2).


1976-1996 – Fungicides with Indirect Modes-of-Action

Increasing environmental and regulatory pressures built interest in fungicides that act on the plant-pathogen interaction rather than the fungus (6). These compounds are not toxic to the isolated fungus, and should be more environmentally benign. It is not even clear if they should be called fungicides since they do not kill fungi directly. The first such compound developed was tricyclazole, introduced in 1976. This systemic fungicide (as well as the newer carpropamid) inhibits melanin biosynthesis, which is required for penetration of the leaf by the appressorium of some fungi (24). Utility is limited mainly to rice blast. Quinoxyfen, a compound from Dow AgroSciences that is highly specific for powdery mildews, also acts by inhibiting the fungus’ ability to initiate infection. Molecular studies suggest that quinoxyfen disrupts the infection process by inhibiting early fungus-plant signaling events and interfering with the fungus’ ability to make the morphological changes necessary for infection (10).

Other fungicides have been commercialized that act through stimulation of the plant’s natural defense response. Probenazole is a systemic compound that indirectly controls rice blast and some bacterial rice diseases. It stimulates the accumulation of toxins and enzymes associated with systemic acquired resistance in rice, but is ineffective in other cereals (14,22). Acibenzolar-S-methyl has the widest spectrum of activity among the non-fungitoxic compounds developed to date. It is active against various fungi, bacteria, and viruses and is highly mobile, with both acropetal and basipetal transport, but is rapidly metabolized (9). It stimulates the plant’s natural defense system, and must be applied as a protectant treatment several days before infection. It has been developed for use against powdery mildews in cereals, rice blast, sigatoka diseases of banana, and blue mold of tobacco (9).

A challenge for treatments that elicit resistance responses in plants is the potential reduction of yield. Alteration of the production of secondary metabolites in plants has a demonstrated fitness cost in some cases, resulting in diminished plant growth (13). This yield drag in the absence of disease may limit the future development of compounds that alter plant metabolism, especially if the compound must be applied before disease pressure is significant.

Because these compounds do not place selection pressure directly on fungal growth, they were expected to be more durable than conventional fungicides and unlikely to stimulate resistance development. Resistance has developed, however, for some compounds with indirect modes of action. Tricyclazole has remained effective for three decades, but resistance rapidly developed to carpropamid (24), despite both being inhibitors of melanin biosynthesis. Resistance to quinoxyfen developed in the wheat powdery mildew population in Europe after more than five years of intensive use (12). On the other hand, the compounds which act by stimulating host resistance have remained effective.


Summary

Fungicides have changed the nature of agriculture. Each key invention was rapidly incorporated into farming practice and raised farmers’ expectations for the next breakthrough in performance. The success of these breakthroughs has been attenuated in some cases by development of resistance in the targeted fungi. Our experiences with fungicide resistance have spurred improvements in fungicide stewardship.


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