Open AccessMilbemycin A4 oxime as a probe of azole transport in Candida glabrata
Author(s) -
Walker Bryan,
Izumikawa Koichi,
Tsai HuieFung,
Bennett John E.
Publication year - 2014
Publication title -
fems yeast research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.991
H-Index - 92
eISSN - 1567-1364
pISSN - 1567-1356
DOI - 10.1111/1567-1364.12164
Subject(s) - azole , candida glabrata , efflux , biology , major facilitator superfamily , transporter , oxime , atp binding cassette transporter , pharmacology , microbiology and biotechnology , biochemistry , candida albicans , antifungal , gene
Azole resistance in Candida glabrata , a pathogenic yeast, has prompted studies of compounds that have therapeutic potential by reversing azole resistance. Milbemycin A4 oxime blocked azole efflux and enhanced azole susceptibility fourfold in 28 clinical isolates of C. glabrata . Specificity of the milbemycin A4 oxime effect depended on the drug transporter and the substrate being effluxed. The major effect of milbemycin A4 oxime was inhibition of azole and rhodamine 6G efflux by the ATP ‐binding cassette ( ABC ) transporters Cg CDR 1 and PDH 1 . Milbemycin A4 oxime effect did not extend to oligomycin, transported by the ABC transporter YOR 1 or to benomyl, transported by the major facilitator superfamily transporter, Cg FLR 1 . Milbemycin A4 oxime did not suppress transcription of Cg CDR 1 but increased Cg CDR 1 expression 126‐fold. Selectivity of the effect is compatible with the concept that milbemycin A4 oxime may interact directly with one or more drug‐binding sites of the major azole transporters.