The Molecular Basis of the Intrinsic and Acquired Resistance to Azole Antifungals in Aspergillus fumigatus.

ABSTRACT: Aspergillus fumigatus is intrinsically resistant to the widely used antifungal fluconazole, and therapeutic failure can result from acquired resistance to voriconazole, the primary treatment for invasive aspergillosis. The molecular basis of substrate specificity and innate and acquired resistance of A. fumigatus to azole drugs were addressed using crystal structures, molecular models, and expression in Saccharomyces cerevisiae of the sterol 14α-demethylase isoforms AfCYP51A and AfCYP51B targeted by azole drugs, together with their cognate reductase AfCPRA2 and AfERG6 (sterol 24-C-methyltransferase). As predicted by molecular modelling, functional expression of CYP51A and B required eburicol and not lanosterol. A crowded conformationally sensitive region involving the

SUBMITTER: Hosseini P 

PROVIDER: S-EPMC11678245 | biostudies-literature | 2024 Nov

REPOSITORIES: biostudies-literature