Histidine Kinase Inhibitors

Dicarboximides and phenylpyrroles have been mainly used to control diseases caused by fungal strains that belong to the genera Botrytis, Sclerotinia, Monilinia, and Alternaria. Both types of fungicides overactivate Hog-like mitogen-activated protein kinases in the osmotic signal transduction pathway and result in cell death. Cross-resistance among dicarboximides, phenylpyrroles, and aromatic hydrocarbons has been observed in most laboratory Botrytis cinerea-resistant mutants, which are generally hyperosmotic sensitive. However, such resistant strains have rarely been isolated from the fields. All dicarboximide-resistant field isolates contained point mutations in a putative osmosensor histidine kinase BcOS1/Daf1, did not show cross-resistance to phenylpyrroles, and were insensitive to osmotic stress. In contrast, Alternaria field-resistant strains carried various mutations, including null mutations, in their osmosensor histidine kinase genes. The introduction of several new fungicides against B. cinerea, such as anilinopyrimidine fungicides, fenhexamid, QoIs, and succinate dehydrogenase inhibitors, reduced the use of dicarboximides, thereby reducing the populations of dicarboximide-resistant strains. However, several types of multidrug resistance strains, in which efflux pumps are activated, have emerged. Gain-of-function mutations of the transcription factor Mrr1, which leads to an overexpression of the ATP-binding cassette transporter AtrB, confers reduced sensitivities to some fungicides, including fludioxonil and cyprodinil. In addition, strains that overexpress the major facilitator superfamily transporter mfsM2 by promoter rearrangements lead to reduced sensitivities to iprodione, fenhexamid, and cyprodinil. Therefore, in addition to target modifications of BcOS1, multidrug resistance caused by the overexpression of drug transporters is another resistance mechanism in B. cinerea against dicarboximides and phenylpyrroles.