Genetic interaction analysis of transcription factors and in the regulation of respiration and fluconazole susceptibility.

is the second most common cause of invasive candidiasis and is widely known to have reduced susceptibility to fluconazole relative to many other spp. Upc2A is a transcription factor that regulates ergosterol biosynthesis gene expression under conditions of sterol stress such as azole drug treatment or hypoxia. Through an microevolution experiment, we found that loss-of-function mutants of the ATF/CREB transcription factor suppresses the fluconazole hyper-susceptibility of the ∆ mutant. Here, we confirm that the ∆ ∆ mutants are resistant to fluconazole but not to hypoxia relative to the ∆ mutant. Sterol analysis of these mutants indicates that this suppression phenotype is not due to restoration of ergosterol levels in the ∆ ∆ mutant. Furthermore, increased expression of , the efflux pump implicated in the vast majority of azole-resistant strains, does not account for the suppression phenotype. Instead, our data suggest that this effect is due in part to increased expression of the adhesin , which has been shown by others to reduce fluconazole susceptibility in . In addition, we find that loss of both and reduces the expression of mitochondrial and respiratory genes and that this also contributes to the suppression phenotype as well as to the resistance of ∆ to fluconazole. These latter data further emphasize the connection between mitochondrial function and azole susceptibility.