A novel multidrug efflux transporter gene of the major facilitator superfamily from Candida albicans (FLU1) conferring resistance to fluconazole

Azole resistance in Candida albicans can be mediated by several resistance mechanisms. Among these, alterations of the azole target enzyme and the ove rexpression of multidrug efflux transporter genes are the most frequent. To identify additional putative azole resistance genes in C. albicans, a geno mic library from this organism was screened for complementation of fluconaz ole hypersusceptibility in Saccharomyces cerevisiae YKKB-13 lacking the ABC (ATP-binding cassette) transporter gene PDR5. Among the C. albicans genes obtained, a new gene was isolated and named FLU1 (fluconazole resistance). The deduced amino acid sequence of FLU1 showed similarity to CaMDR1 (former ly BENr), a member of the major facilitator superfamily of multidrug efflux transporters. The expression of FLU1 in YKKB-13 mediated not only resistan ce to fluconazole but also to cycloheximide among the different drugs teste d. The disruption of FLU1 in C. albicans had only a slight effect on flucon azole susceptibility; however it resulted in hypersusceptibility to mycophe nolic acid, thus suggesting that this compound could be a substrate for the protein encoded by FLU1. Disruption of FLU1 in a background of C. albicans mutants with deletions in several multidrug efflux transporter genes, incl uding CDR1, CDR2 and CaMDR1, resulted in enhanced susceptibility to several azole derivatives. FLU1 expression did not vary significantly between seve ral pairs of azole-susceptible and azole-resistant C. albicans clinical iso lates. Therefore, FLU1 seems not to be required for the development of azol e resistance in clinical isolates.