Multidrug Transporters and Alterations in Sterol Biosynthesis Contribute to Azole Antifungal Resistance in Candida parapsilosis

Abstract

ABSTRACTWhile much is known concerning azole resistance inCandida albicans, considerably less is understood aboutCandida parapsilosis, an emerging species ofCandidawith clinical relevance. We conducted a comprehensive analysis of azole resistance in a collection of resistantC. parapsilosisclinical isolates in order to determine which genes might play a role in this process within this species. We examined the relative expression of the putative drug transporter genesCDR1andMDR1and that ofERG11. In isolates overexpressing these genes, we sequenced the genes encoding their presumed transcriptional regulators,TAC1,MRR1, andUPC2, respectively. We also sequenced the sterol biosynthesis genesERG3andERG11in these isolates to find mutations that might contribute to this phenotype in thisCandidaspecies. Our findings demonstrate that the putative drug transporters Cdr1 and Mdr1 contribute directly to azole resistance and suggest that their overexpression is due to activating mutations in the genes encoding their transcriptional regulators. We also observed that the Y132F substitution inERG11is the only substitution occurring exclusively among azole-resistant isolates, and we correlated this with specific changes in sterol biosynthesis. Finally, sterol analysis of these isolates suggests that other changes in sterol biosynthesis may contribute to azole resistance inC. parapsilosis.