Resistance to azole antifungal agents in can be mediated by multidrug efflux transporters. In a previous study, we identified at least two such transporters, Cdr1p and Benp, which belong to the class of TP-inding assette (ABC) transporters and of major facilitators, respectively. To isolate additional factors potentially responsible for resistance to azole antifungal agents in the hypersusceptibility of a multidrug transporter mutant, δ, to these agents was complemented with a genomic library. Several new genes were isolated, one of which was a new ABC transporter gene called ( rug esistance). The protein Cdr2p encoded by this gene exhibited 84% identity with Cdr1p and could confer resistance to azole antifungal agents, to other antifungals (terbinafine, amorolfine) and to a variety of metabolic inhibitors. The disruption of in the strain CAF4-2 did not render cells more susceptible to these substances. When the disruption of was performed in the background of a mutant in which was deleted, the resulting double δ δ mutant was more susceptible to these agents than the single δ mutant. The absence of hypersusceptibility of the single δ mutant could be explained by the absence of mRNA in azole-susceptible strains. was overexpressed, however, in clinical isolates resistant to azole antifungal agents as described previously for but to levels exceeding or equal to those reached by Interestingly, expression was restored in δ mutants reverting spontaneously to wild-type levels of susceptibility to azole antifungal agents. These data demonstrate that plays an important role in mediating the resistance of to azole antifungal agents.


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