Participation of the ABC Transporter in Azole Resistance of .

is an opportunistic pathogen in humans that causes infrequent but difficult-to-treat diseases. Antifungal drugs are used in the clinic to treat infections, however, this fungus can rapidly acquire antifungal resistance to all known antifungal drugs (multidrug resistance). acquires azole resistance by gain-of-function (GOF) mutations in the transcriptional regulator . controls the expression of a major facilitator transporter () that is important for fluconazole resistance. Here, we addressed the role of the ATP Binding Cassette (ABC) transporter as additional mediator of azole resistance in expression in isolates with GOF mutations was higher compared to wild types, which suggests that is an additional (direct or indirect) target of . deletion in the azole-resistant isolate P3 (V688G GOF) revealed that MICs of long-tailed azoles, itraconazole and posaconazole, were decreased compared to P3, which is consistent with the role of this ABC transporter in the efflux of these azoles. Fluconazole MIC was only decreased when was deleted in the background of an Δ mutant from P3, which underpins the dominant role of in the resistance of the short-tailed azole fluconazole. With R6G efflux readout as Cdr1 efflux capacity, our data showed that R6G efflux was increased in P3 compared to an azole-susceptible wild type parent, and diminished to background levels in mutant strains lacking . Milbemycin oxim A3, a known inhibitor of fungal ABC transporters, mimicked efflux phenotypes of Δ mutants. We therefore provided evidence that is an additional mediator of azole resistance in and that regulation is dependent on and associated GOF mutations.