1. Induction of Aspergillus fumigatus zinc cluster transcription factor OdrA/Mdu2 provides combined cellular responses for oxidative stress protection and multiple antifungal drug resistance.
- Author
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Sasse C, Bastakis E, Bakti F, Höfer AM, Zangl I, Schüller C, Köhler AM, Gerke J, Krappmann S, Finkernagel F, Harting R, Strauss J, Heimel K, and Braus GH
- Subjects
- Drug Resistance, Multiple, Fungal genetics, Azoles pharmacology, Drug Resistance, Fungal genetics, Aspergillus fumigatus genetics, Aspergillus fumigatus drug effects, Aspergillus fumigatus metabolism, Oxidative Stress, Antifungal Agents pharmacology, Transcription Factors genetics, Transcription Factors metabolism, Gene Expression Regulation, Fungal, Fungal Proteins genetics, Fungal Proteins metabolism
- Abstract
Importance: An overexpression screen of 228 zinc cluster transcription factor encoding genes of A. fumigatus revealed 11 genes conferring increased tolerance to antifungal drugs. Out of these, four oxidative stress and drug tolerance transcription factor encoding odr genes increased tolerance to oxidative stress and antifungal drugs when overexpressed. This supports a correlation between oxidative stress response and antifungal drug tolerance in A. fumigatus . OdrA/Mdu2 is required for the cross-tolerance between azoles, polyenes, and oxidative stress and activates genes for detoxification. Under oxidative stress conditions or when overexpressed, OdrA/Mdu2 accumulates in the nucleus and activates detoxifying genes by direct binding at their promoters, as we describe with the mdr1 gene encoding an itraconazole specific efflux pump. Finally, this work gives new insights about drug and stress resistance in the opportunistic pathogenic fungus A. fumigatus ., Competing Interests: The authors declare no conflict of interest.
- Published
- 2023
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