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RttA, a Zn2-Cys6 transcription factor in Aspergillus fumigatus, contributes to azole resistance

Summary

Researchers discovered that a fungal protein called RttA plays a key role in helping Aspergillus fumigatus resist azole antifungal drugs. By studying mutant strains, they found that RttA acts as a master switch controlling genes that reduce the effectiveness of antifungal medications. This finding is important because it could help develop new strategies to treat fungal infections that are becoming resistant to current medications.

Background

Aspergillus fumigatus is a ubiquitous fungal pathogen causing aspergillosis with high mortality despite antifungal treatment. Azole resistance in A. fumigatus is increasing due to environmental exposure to agricultural fungicides and prolonged clinical use. Previous studies identified RttA as a protein involved in azole susceptibility, but its molecular function remained unknown.

Objective

To elucidate the role of RttA in azole resistance by conducting RNA-Seq analysis and functional studies using RttA deletion and overexpression strains. The study aimed to characterize RttA as a transcription factor and identify genes regulated by RttA that contribute to azole resistance.

Results

RttA was reannotated as a Zn2-Cys6 fungal-type transcription factor containing a GAL4-like DNA-binding domain. The ΔrttA strain showed increased susceptibility to itraconazole and voriconazole, while rttA-overexpressing strains showed decreased susceptibility. Six genes including ggtA (γ-glutamyl transpeptidase) and facC were identified as putatively regulated by RttA with UPC2-binding motifs in their promoter regions.

Conclusion

RttA is a Zn2-Cys6 transcription factor that contributes to azole resistance in A. fumigatus by regulating multiple genes. Understanding RttA’s role and its target genes provides insights into azole resistance mechanisms and identifies RttA as a potential target for developing new antifungal strategies against A. fumigatus.
  • Published in:Microbiology Spectrum,
  • Study Type:Experimental Research,
  • Source: PMID: 40839779, DOI: 10.1128/spectrum.01810-25
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