RttA, a Zn ₂ -Cys ₆ transcription factor in Aspergillus fumigatus , contributes to azole resistance

Aspergillus fumigatus is a common environmental fungus and the leading cause of aspergillosis, an opportunistic infection in humans and animals. The mortality rate of aspergillosis remains high despite antifungal treatments, with azole antifungals, such as voriconazole, being the primary treatment. However, resistance to azoles is increasing, partly because of environmental exposure to agricultural fungicides. In a previous study, we identified the protein RttA to be involved in azole susceptibility. To further understand the role of RttA in azole resistance, we conducted RNA-Seq analysis and functional analyses by constructing RttA deletion and overexpression strains. The transcriptome data revealed that RttA contains a Zn 2 -Cys 6 domain and may function as a transcription factor. Furthermore, six genes, including a γ-glutamyl transpeptidase gene ( ggtA ) and a homolog of factor C ( facC ), were shown to be putatively regulated by RttA. These findings suggest that RttA is involved in azole resistance by regulating several genes, highlighting its potential as a target for developing antifungal strategies against A. fumigatus . IMPORTANCE This study identified RttA as a Zn 2 -Cys 6 transcription factor in Aspergillus fumigatus , a critical pathogen that causes aspergillosis. RttA influences azole susceptibility. Our results demonstrated that the deletion of RttA increases susceptibility to azoles, whereas its overexpression enhances resistance. This discovery is crucial because the mechanism underlying azole resistance has not yet been fully elucidated. Hence, understanding the role of RttA provides insights into resistance mechanisms and potential targets for new therapeutic strategies, thereby addressing the urgent need for effective treatments against azole-resistant A. fumigatus strains.