Structural basis of HapE^P88L-linked antifungal triazole resistance in <i>Aspergillus fumigatus</i>

Abstract

Azoles are first-line therapeutics for human and plant fungal infections, but their broad use has promoted the development of resistances. Recently, a pan-azole-resistant clinical <i>Aspergillus fumigatus</i> isolate was identified to carry the mutation P88L in subunit HapE of the CCAAT-binding complex (CBC), a conserved eukaryotic transcription factor. Here, we define the mechanistic basis for resistance in this isolate by showing that the HapE^P88L mutation interferes with the CBC's ability to bend and sense CCAAT motifs. This failure leads to transcriptional derepression of the <i>cyp51A</i> gene, which encodes the target of azoles, the 14-α sterol demethylase Cyp51A, and ultimately causes drug resistance. In addition, we demonstrate that the CBC-associated transcriptional regulator HapX assists <i>cyp51A</i> repression in low-iron environments and that this iron-dependent effect is lost in the HapE^P88L mutant. Altogether, these results indicate that the mutation HapE^P88L confers increased resistance to azoles compared with wt <i>A. fumigatus</i>, particularly in low-iron clinical niches such as the lung.