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Antifungal therapy failure can be associated with increased resistance to the employed antifungal agents.Candida glabrata , the second most common cause of invasive candidiasis, is intrinsically less susceptible to the azole class of antifungals and accounts for 15% of allCandida bloodstream infections. Here, we show thatC. glabrata MED2 (CgMED2 ), which codes for a tail subunit of the RNA polymerase II Mediator complex, is required for resistance to azole antifungal drugs inC. glabrata . An inability to transcriptionally activate genes encoding a zinc finger transcriptional factor, CgPdr1, and multidrug efflux pump, CgCdr1, primarily contributes to the elevated susceptibility of theCgmed2 Δ mutant toward azole antifungals. We also report for the first time that theCgmed2 Δ mutant exhibits sensitivity to caspofungin, a constitutively activated protein kinase C-mediated cell wall integrity pathway, and elevated adherence to epithelial cells. The increased adherence of theCgmed2 Δ mutant was attributed to the elevated expression of theEPA1 andEPA7 genes. Further, our data demonstrate thatCgMED2 is required for intracellular proliferation in human macrophages and modulates survival in a murine model of disseminated candidiasis. Lastly, we show an essential requirement for CgMed2, along with the Mediator middle subunit CgNut1 and the Mediator cyclin-dependent kinase/cyclin subunit CgSrb8, for the high-level fluconazole resistance conferred by the hyperactive allele of CgPdr1. Together, our findings underscore a pivotal role for CgMed2 in basal tolerance and acquired resistance to azole antifungals.

Pivotal Role for a Tail Subunit of the RNA Polymerase II Mediator Complex CgMed2 in Azole Tolerance and Adherence in Candida glabrata