Modulators of membrane drug transporters potentiate the activity of the DMI fungicide oxpoconazole against Botrytis cinerea.
Modulators known to reduce multidrug resistance in tumour cells were tested for their potency to synergize the fungitoxic activity of the fungicide oxpoconazole, a sterol demethylation inhibitor (DMI), against Botrytis cinerea Pers. Chlorpromazine, a phenothiazine compound known as a calmodulin antagonist, appeared the most potent compound. Tacrolimus, a macrolide compound with immunosuppressive activity, was also active. The synergism of chlorpromazine negatively correlated with the sensitivity of the parent strain and mutants of B. cinerea. The synergism was highest in a mutant that overexpressed the ATP-binding cassette transporter BcatrD, known to transport DMI fungicides such as oxpoconazole. The synergism of chlorpromazine positively correlated with its potency to enhance the accumulation of oxpoconazole in BcatrD mutants. These results indicate that chlorpromazine is a modulator of BcatrD activity in B. cinerea and suggest that mixtures of DMI fungicides with modulators may represent a perspective for the development of new resistance management strategies.
Hayashi
Keisuke
K
Laboratory of Phytopathology, Wageningen University, PO Box 8025, 6700 EE Wageningen, The Netherlands.
Schoonbeek
Henk-jan
HJ
De Waard
Maarten A
MA
D020171:Botrytis / Q000187:drug effects* / Q000235:genetics; D002147:Calmodulin / Q000037:antagonists & inhibitors; D002746:Chlorpromazine / Q000494:pharmacology; D004357:Drug Synergism; D005659:Fungicides, Industrial / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D005838:Genotype; D007093:Imidazoles / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D026901:Membrane Transport Proteins / Q000378:metabolism*; D015394:Molecular Structure; D010574:Pesticide Synergists / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*
D002147:Calmodulin; D005659:Fungicides, Industrial; D007093:Imidazoles; D026901:Membrane Transport Proteins; D010574:Pesticide Synergists; C481307:oxpoconazole; D002746:Chlorpromazine