SREBP-Dependent Triazole Susceptibility in Aspergillus fumigatus Is Mediated through Direct Transcriptional Regulation oferg11A(cyp51A)

Abstract

ABSTRACTAs triazole antifungal drug resistance during invasiveAspergillus fumigatusinfection has become more prevalent, the need to understand mechanisms of resistance inA. fumigatushas increased. The presence of twoerg11(cyp51) genes inAspergillusspp. is hypothesized to account for the inherent resistance of this mold to the triazole fluconazole (FLC). Recently, anA. fumigatusnull mutant of a transcriptional regulator in the sterol regulatory element binding protein (SREBP) family, the ΔsrbAstrain, was found to have increased susceptibility to FLC and voriconazole (VCZ). In this study, we examined the mechanism engendering the observed increase inA. fumigatustriazole susceptibility in the absence of SrbA. We observed a significant reduction in theerg11Atranscript in the ΔsrbAstrain in response to FLC and VCZ. Transcript levels oferg11Bwere also reduced but not to the extent oferg11A. Interestingly,erg11Atranscript levels increased upon extended VCZ, but not FLC, exposure. Construction of anerg11Aconditional expression strain in the ΔsrbAstrain was able to restoreerg11Atranscript levels and, consequently, wild-type MICs to the triazole FLC. The VCZ MIC was also partially restored upon increasederg11Atranscript levels; however, total ergosterol levels remained significantly reduced compared to those of the wild type. Induction of theerg11Aconditional strain did not restore the hypoxia growth defect of the ΔsrbAstrain. Taken together, our results demonstrate a critical role for SrbA-mediated regulation of ergosterol biosynthesis and triazole drug interactions inA. fumigatusthat may have clinical importance.