Negatively correlated cross resistance

Chapman, R.B. and Penman, D.R., Negatively correlated cross-resistance to a synthetic pyrethroid in organophosphorus-resistant Tetranychus urticae, Nature, 281, 298,1979. 

Use of compounds that display negatively-correlated cross-resistance. 

Cross Resistance. This seemingly simple term is also subject to various interpretations. It is probably best defined as resistance of an organism to two or more toxicants (with the implication that the normal population is sensitive to both). Recently the added qualifier positive or positively correlated cross resistance has been suggested, since there are instances where resistance to one toxicant is accompanied by increased sensitivity to another, which are then termed negative or negatively correlated cross resistance. (For an example, see Fujimura, Ishii, this volume.)... 

In principle, one of the most effective means to cope with resistance of plant pathogens is the use of fungicides to which resistant strains show negatively correlated cross resistance. However, until now this strategy has seen limited use in practice, principally for lack of suitably effective compounds. Herein we discuss one of the first practically useful examples of negatively correlated cross resistance, and report on its genetic and molecular basis. 

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). 

Genetic studies of negatively correlated cross resistance between benzimidazoles and N-phenylcarbamates. 

To elucidate the mechanism of negatively correlated cross resistance and mode of action of diethofencarb, we isolated diethofencarb resistant mutants from mutagenized F914 strain. 

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. 

Considerable interest has developed in resistance management through the use of 1) compounds that are more active against fungicide-resistant biotypes than their sensitive counterparts (i.e., the resistant biotypes exhibit negatively-correlated cross resistance) and 2) compounds that interfere with the resistance mechanism (i.e., synergists). Both approaches to resistance control have been reviewed by De Waard (24,45). 

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]. 

Table 4. Negatively correlated cross-resistance in carboxanilide.

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