Titel: Identification of azole tolerance-affecting transcription factors and ABC transporters in Aspergillus fumigatus
ID: 10/EKV
Art: Abstractautor
Session: Workshop 02
Eukaryotic Pathogens incl. DMykG Lecture (FG EK)

Referent: Johannes Wagener (Würzburg\München, Würzburg, München)

Abstract - Text

Aspergillus fumigatus is an airborne fungal pathogen and the primary cause of invasive aspergillosis. This severe infection is associated with high mortality rates and is a major threat for immunocompromised patients. Invasive aspergillosis is typically treated with azole antifungals. However, the emergence of azole resistance is challenging this therapeutic approach. The only currently known mechanisms that mediate azole resistance in A. fumigatus are related to mutations in the azole target structure CYP51 and its promoter. Mitochondrial dysfunctions can affect the azole susceptibility of molds. We have previously shown that disruption of mitochondrial fission and fusion increases the azole tolerance of A. fumigatus. To further explore the mechanism behind this altered azole susceptibility, we analyzed the transcriptome of the fission/fusion mutant. We identified multiple efflux pumps and transcription factors that are differentially expressed in the fission/fusion mutant. The promoters of several candidate ATP-binding cassette (ABC) transporters and transcription factors were subsequently replaced with a conditional doxycycline-inducible promoter system. Phenotypic characterization of the conditional mutants revealed the ability of five ABC transporters and seven transcription factors to affect the azole susceptibility of A. fumigatus. The identified genes could be involved in non-CYP51-dependent azole resistance mechanisms.