Benzimidazole-resistant strains, negatively correlated cross resistance

Leroux and Gredt reported that benzimidazole-resistant strains of Botrytis cinerea and Penicillium expansum exhibited negatively correlated cross resistance to herbicidal N-phenylcarbamates such as barban, chlorpropham, and chlorbufam (10, 11, 12). Based on their observation, Sumitomo scientists evaluated many examples of N-phenylcarbamates to search for compounds with potent fungitoxicity and no phytotoxicity. This effort was eventually successful, leading to new fungicides such as MDPC ( , 21 ) and diethofencarb (14, 23, 24) (Figure 2). 

We used N. crassa as a model fungus and attempted to elucidate the mechanism of negatively correlated cross resistance between benzimidazoles and N-phenylcarbamates. MBC resistant mutants were isolated from the wild type strain of N. crassa by UV treatment. Selection of the MBC resistant mutants was carried out on medium containing 50ppm MBC. MBC (carbendazim), the degradation product of benomyl and thiophanate-methyl, appears to be the active form in fungi (1). 

However difference aspect was observed in resistance to MBC between N. crassa isolates in laboratory and B. cinerea isolates from the field. Laboratory-generated mutants of N. crassa showed various levels of resistance to MBC, and a specific one showed negatively correlated cross resistance to diethofencarb. Others showed double resistance to these chemicals. On the other hand, most of the benzimidazole resistants isolated from the field, especially in in the case of B. cinerea, were supersensitive to diethofencarb. This difference between laboratory and field strains may derive from a difference in fitness among the resistant strains of the plant pathogen. 

Recently, the carbamate fungicide diethofencarb (15) which takes advantage of a negatively-correlated cross-resistance phenomenon, has been developed as a potent fungicide against benzimidazole-resistant fungi [45, 46]. Studies on the mode of action of 15 have revealed that P-tubulin in the benzimidazole-resistant strain F914 of N. crassa has an affinity for diethofencarb (15) rather than for benzimidazole derivatives, whilst in a wild-type strain of N. crassa there was an inverse affinity [46, 47]. 

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