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Genome-wide screening of 228 zinc cluster transcription factor encoding genes by overexpression in\n Aspergillus fumigatus<\/jats:italic>\n revealed 11 genes which provided increased tolerance to the broadly applied azole voriconazole or to the polyene amphotericin B or to both. These include four\n o<\/jats:underline>\n xidative stress and\n d<\/jats:underline>\n rug\n r<\/jats:underline>\n esistance genes (\n odrA-D<\/jats:italic>\n ) genes encoding factors, which provide broad cellular stress protection. Thereby, the corresponding fungal OdrA\/Mdu2- and AtrR\/OdrD-dependent genetic networks are interconnected. OdrA\/Mdu2 activates\n atrR<\/jats:italic>\n \/\n odrD<\/jats:italic>\n transcription by direct binding to the promoter, whereas AtrR\/OdrD functions as repressor of\n odrA<\/jats:italic>\n \/\n mdu2<\/jats:italic>\n expression.\n odrA<\/jats:italic>\n \/\n mdu2<\/jats:italic>\n overexpression provides combined resistance to amphotericin B, voriconazole, itraconazole, and reactive oxygen species generated by menadione. OdrA\/Mdu2-mediated itraconazole resistance is evoked by direct regulation of the transporter encoding gene\n mdr1<\/jats:italic>\n . Oxidative stress-inducing substances like amphotericin B and menadione promote OdrA\/Mdu2 accumulation in the nucleus to regulate stress response genes like\n mdr1<\/jats:italic>\n and the putative glutathione-S-transferase encoding gene\n gstD<\/jats:italic>\n . The expression levels and external stress conditions fostering nuclear accumulation of OdrA\/Mdu2 determine the regulation of the target genes. Hence, OdrA\/Mdu2 provides a combined adaptation strategy for survival in nature or within a potential host, where this fungus represents the most common agent for human mold pneumonia worldwide. The OdrA\/Mdu2 controlled genetic network highlights the tight connection between oxidative stress response and antifungal drug adaption to secure\n A. fumigatus<\/jats:italic>\n survival in various hostile environments.\n <\/jats:p>\n \n IMPORTANCE<\/jats:title>\n \n An overexpression screen of 228 zinc cluster transcription factor encoding genes of\n A. fumigatus<\/jats:italic>\n revealed 11 genes conferring increased tolerance to antifungal drugs. Out of these, four oxidative stress and drug tolerance transcription factor encoding\n odr<\/jats:italic>\n genes increased tolerance to oxidative stress and antifungal drugs when overexpressed. This supports a correlation between oxidative stress response and antifungal drug tolerance in\n A. fumigatus<\/jats:italic>\n . 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\n mdr1<\/jats:italic>\n gene encoding an itraconazole specific efflux pump. Finally, this work gives new insights about drug and stress resistance in the opportunistic pathogenic fungus\n A. fumigatus<\/jats:italic>\n .\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1128\/mbio.02628-23","type":"journal-article","created":{"date-parts":[[2023,11,20]],"date-time":"2023-11-20T14:03:04Z","timestamp":1700488984000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":22,"title":["Induction of\n Aspergillus fumigatus<\/i>\n zinc cluster transcription factor OdrA\/Mdu2 provides combined cellular responses for oxidative stress protection and multiple antifungal drug resistance"],"prefix":"10.1128","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2612-1313","authenticated-orcid":false,"given":"Christoph","family":"Sasse","sequence":"first","affiliation":[{"name":"Department of Molecular Microbiology and Genetics and G\u00f6ttingen Center for Molecular Biosciences (GZMB), Institute of Microbiology 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