Point mutation or overexpression of Aspergillus fumigatus Cyp51B, encoding lanosterol 14α-sterol demethylase, leads to triazole resistance

Aspergillus fumigatus is the most common cause of invasive fungal mold infections in immunocompromised individuals. Current antifungal treatment relies heavily on the triazole antifungals which inhibit fungal Erg11/Cyp51 activity and subsequent ergosterol biosynthesis. However, resistance, due primarily to cyp51 mutation, is rapidly increasing. A. fumigatus contains two Cyp51 isoenzymes, Cyp51A and Cyp51B. Overexpression and mutation of Cyp51A is a major cause of triazole resistance in A. fumigatus. The role of Cyp51B in generating resistance is unclear. Here, we show that overexpression or mutation of cyp51B results in triazole resistance. We demonstrate that introduction of a G457S Cyp51B mutation identified in a resistant clinical isolate results in voriconazole resistance in a naive recipient strain. Our results indicate that mutations in cyp51B resulting in clinical resistance do exist and should be monitored.