There is currently no active FRAC Working Group on benzimidazoles. Instead an informal network of experts around the world has been formed. The role of the FRAC benzimidazole Expert Forum is to optimize information exchange around the globe on benzimidazole resistance. Request for information can be addressed either to the chairman or directly to individual members (“experts”) of the network. A list of experts is provided at the end of this page.

Benzimidazoles represent the beginning of serious resistance problems in fungicides. A few years after commercialisation, loss of disease control with benzimidazole fungicides was recorded in many crops, especially with pathogens having numerous cycles per year, such as Botrytis cinerea. For pathogens having only 1-2 cycles per year, resistance developed after a longer period of use, e.g., more than 10 years for cereal eyespot caused by Tapesia spp. Nevertheless, benzimidazoles are still used widely and continue to be valuable fungicides in global agricultural production.

Since commercialisation at least 100 species of fungi have developed some degree of resistance to benzimidazoles. Table 1 gives an overview of published information relative to resistance development in pathogenic fungi affecting economically important crops globally.

Cases of resistance to benzimidazole on key pathogens in economically important crops.

Many cellular processes (eg maintenance of cell shape, cell division, and intracellular movement of organelles) in eukaryotic organisms depend on proper functioning of the cytoskeleton. Microtubules, one type of cytoskeleton filament, regulate organelle position and movement within the cell. Microtubules consist of long, hollow cylinders of repeating dimers of a- and ß-tubulin. Although highly conserved, the amino acid sequences of the tubulin genes as well as sensitivity to inhibitors may vary significantly without destroying gene function. In fact sufficient diversity is present to allow selection of a wide range of inhibitors, target organisms, as well as host selectivity necessary for successful therapeutic use.

Benzimidazoles are potent inhibitors of ß-tubulin polymerization in many species of fungi and have been used for plant disease control since the late 1960’s. Although direct interactions with ß-tubulin seem to be the predominant inhibitory processes for this chemical class, interactions with other forms of tubulin as well as differential interactions with tubulin in the free and polymerized states also have been reported.

Benzimidazole fungicides control a remarkably broad spectrum of plant pathogenic fungi. But they do not control Oomycete organisms that are responsible for downy mildew diseases of many crops and late blight, an important disease of solanaceous crops. Of interest is the recent identification of benzamide fungicides that selectively affect tubulin and microtubule interactions in Oomycetes without significant inhibitory effects in true fungi.

Studies have demonstrated that fungicidal activity and resistance are determined by affinity of specific inhibitors for target sites on ß-tubulin. Other possible resistance mechanisms, like increased metabolism or reduced uptake of inhibitors, do not appear to be important factors for this area of chemistry.

Alterations in the a-tubulin gene affecting sensitivity to benzimidazole fungicides usually are of little practical significance for resistance management since they result in increased sensitivity to inhibitors. Resistance to benzimidazole fungicides is related primarily to specific alterations in the binding sites on the ß-tubulin protein. Approximately 10 mutations conferring resistance to benzimidazoles have been identified in the ß-tubulin gene in laboratory studies with a wide range of different fungi. Many of these mutations also reduce fitness (eg increased sensitivity to heat or cold temperatures). With a few exceptions, loss of field performance has been associated with 5 target site mutations, at codons 6, 50, 198, 200, 240. The most common and significant mutations occur at codons 198 and 200. At codon 198, mutants vary from moderately to very highly resistant depending on the specific amino acid replacing glutamic acid present in the sensitive wild type. At codon 200, resistant isolates are characterized by a single substitution of phenylalanine by tyrosine. Not only are these mutants resistant to benzimidazole inhibitors, but they are mostly fit and fully capable of survival in the absence of the fungicide.

For practical applications, fungal isolates resistant to one benzimidazole fungicide usually are resistant to other members of this chemical class. Therefore combinations of various benzimidazole fungicides cannot be used as a resistance management tool. There is no positive cross resistance with commercial fungicides from other chemical classes, therefore combinations of benzimidazoles with companion fungicides with different target sites are an effective means of reducing resistance risk.

The unusual phenomenon of negative cross resistance has been reported between benzimidazole fungicides and two other chemical classes, N-phenylcarbamates and N-phenylformamidoximes. Fungal isolates sensitive to benzimidazoles are resistant to phenylcarbamates, like diethofencarb. Isolates that are resistant to benzimidazoles, however, are sensitive to phenylcarbamates. This phenomenon allows mixtures of these two classes to be used commercially for resistance management in Botrytis cinerea. Although isolates resistant to both classes have been detected, the low frequencies of double resistant isolates results in this mixture remaining effective.

Benzimidazole resistance generally is persistent, remaining stable in some areas 10 years or more after benzimidazole use was stopped. There have been a few exceptions. Benomyl was successfully used for over 10 years in some parts of the United States for cucurbit powdery mildew control even though resistant isolates were first detected before first commercial use of the fungicide. Monitoring demonstrated that the proportion of resistant isolates dropped after reduction of fungicide use and field efficacy was regained. With repeated use, however, the proportion of benomyl-resistant isolates increased and field efficacy decreased to the point where benomyl was no longer highly effective. A similar situation was reported for benzimidazoles used for the control of banana Sigatoka in Latin America.

Due to the widespread incidence of benzimidazole resistance in many fungal populations, good resistance management practices must be implemented as soon as possible in order to delay or prevent further changes in sensitivity in the target pathogens.

There are no specific recommendations for benzimidazoles. Both mixtures and alternations are valid strategies to minimize the risk of resistance development. In case of tank-mixtures, the benzimidazole fungicide must be applied at its label dose together with the appropriate dose of an effective, non-cross-resistant partner fungicide. Benzimidazole-based products must be integrated in a spray program containing fungicides having a different site of action and effective on the target pest. In order to reduce selection pressure, the total number of benzimidazole applications should not exceed that indicated on the product label. The exclusive use of benzimidazole fungicides must be avoided. Post-infection, curative treatments must be reserved for special situations where no alternatives are available.

The above recommendations must be integrated in an overall disease management program combining appropriate methods of cultural, biological as well as chemical disease control. Implementation of the above strategies must take into account the particular characteristics of the crop, pest and geographic area in which the benzimidazole product is to be applied.

Hollomon, D. W., J. A. Butters. 1994. Molecular determinants for resistance to crop protection chemicals. pp. 98-110 in G. Marshall, D. Walters (eds). Molecular Biology in Crop Protection. Chapman & Hall. London.

Ma, Z., M. A. Yoshimura, T. J. Michailides. 2003. Identification and characterization of benzimidazole resistance in Monilinia fructicola from stone fruit orchards in California. Applied & Environ. Microbiol. 69:7145-7152.

Hollomon, D. W., J. A. Butters, H. Barker, L. Hall. 1998. Fungal beta-tubulin, expressed as a fusion protein, binds benzimidazole and phenylcarbamate fungicides. Antimicrobial Agents & Chemotherapy 42:2171-2173.

McGrath, M. T. 2001. Fungicide resistance in cucurbit powdery mildew: experiences and challenges. Plant Disease 85:236-245 .

Delp, C. J. 1995. Benzimidazole and related fungicides. Chap. 14 (pp. 291-303) in Modern Selective Fungicides. ed. H. Lyr. VEB Gustav Fischer Verlag, Jena, and Longman Group UK Ltd., London.

UK Fungicide Resistance Action Group (FRAG) http://www.pesticides.gov.uk/rags.asp

Brown, T. (1992). Methods to evaluate adverse consequences of genetic changes caused by 5 pesticides. In: Scope 49 - Methods to assess adverse effects of pesticides on non-target organisms, Robert G. Tardiff, pp. 236-241.

Davidse L. C. Benzimidazole (1988) Fungicides: Mechanism of Action and resistance. In: Fungicide Resistance in North America, American Phytopathological Society, C. J. Delp Editor pp. 25-30.

Delp C. J. (1988) Resistance management strategies for benzimidazoles. In: Fungicide Resistance in North America, American Phytopathological Society, C. J. Delp Editor pp. 41-43.

Smith C. M. (1988) History of benzimidazole use and resistance. In: Fungicide Resistance in North America, American Phytopathological Society, C. J. Delp Editor pp. 23-24.

Delp, C. J. and H. L. Klopping. (1968) Performance Attributes of New Fungicide and Mite Ovicide Candidate. Plant Disease Reporter 52:95-99.

Jean-Luc Genet
Chairman

DuPont de Nemours (France) S.A.S.
Crop Protection
24, rue du moulin
F-6870 Nambsheim, France
Tel. +33 38 98 32 712
Fax. +33 38 98 32 727
Email: Jean-Luc Genet

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