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Azoles are widely used in antifungal therapy in medicine. Resistance to azoles can occur inCandida albicans principally by overexpression of multidrug transporter geneCDR1 ,CDR2 , orMDR1 or by overexpression ofERG11 , which encodes the azole target. The expression of these genes is controlled by the transcription factors (TFs)TAC1 (involved in the control ofCDR1 andCDR2 ),MRR1 (involved in the control ofMDR1 ), andUPC2 (involved in the control ofERG11 ). Several gain-of-function (GOF) mutations are present in hyperactive alleles of these TFs, resulting in the overexpression of target genes. While these mutations are beneficial toC. albicans survival in the presence of the antifungal drugs, their effects could potentially alter the fitness and virulence ofC. albicans in the absence of the selective drug pressure. In this work, the effect of GOF mutations onC. albicans virulence was addressed in a systemic model of intravenous infection by mouse survival and kidney fungal burden assays. We engineered a set of strains with identical genetic backgrounds in which hyperactive alleles were reintroduced in one or two copies at their genomic loci. The results obtained showed that neitherTAC1 norMRR1 GOF mutations had a significant effect onC. albicans virulence. In contrast, the presence of two hyperactiveUPC2 alleles inC. albicans resulted in a significant decrease in virulence, correlating with diminished kidney colonization compared to that by the wild type. In agreement with the effect on virulence, the decreased fitness of an isolate withUPC2 hyperactive alleles was observed in competition experiments with the wild typein vivo but notin vitro . Interestingly,UPC2 hyperactivity delayed filamentation ofC. albicans after phagocytosis by murine macrophages, which may at least partially explain the virulence defects. Combining theUPC2 GOF mutation with another hyperactive TF did not compensate for the negative effect ofUPC2 on virulence. In conclusion, among the major TFs involved in azole resistance, onlyUPC2 had a negative impact on virulence and fitness, which may therefore have consequences for the epidemiology of antifungal resistance.

Distinct Roles of Candida albicans Drug Resistance Transcription Factors TAC1 , MRR1 , and UPC2 in Virulence