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Hmg1 mutations in Aspergillus fumigatus and their contribution to triazole susceptibility
Teppei Arai1, Takashi Umeyama2, Hidetaka Majima1,3
1Division of Clinical Research, Medical Mycology Research Center, Chiba University, 260-8673, Chiba City, Chiba, Japan.
Abstract:
Triazole-resistant Aspergillus fumigatus is a global health concern. In general, each triazole resistance pattern caused by the specified amino acid substitution of Cyp51A has a typical pattern depending on the mutation site. We evaluated the contribution of both Cyp51A and Hmg1 mutations to atypical triazole resistance in A. fumigatus. We used clinical triazole-resistant A. fumigatus strains collected in Japan and investigated the sequences of cyp51A and hmg1 genes. To delineate the association between the hmg1 mutation and atypical triazole resistance, the mutant hmg1 alleles in clinical multi-azole resistant strains were replaced with the wild-type hmg1 allele by CRISPR/Cas9 system. In our study, the combination of Cyp51A mutation and Hmg1 mutation was shown to additively contribute to triazole resistance. We also demonstrated that the triazole resistance conferred by the Hmg1 mutation showed a different pattern depending on the mutation site, similar to the Cyp51A mutation. Our results indicate that focusing on the phenotypes of multiple genes is essential to clarify the overall picture of the triazole resistance mechanism of A. fumigatus.
Lay Summary:
The number of triazole-resistant Aspergillus fumigatus is increasing. We confirmed thatmutation in a hydroxymethylglutaryl-CoA reductase (Hmg1) in the fungus contributesto the resistance separately from Cyp51A mutation, and that susceptibility patterns aredifferent based on mutation site.
Insights
Triazole resistance in Aspergillus fumigatus is increasing. Mutations in both Cyp51A and hydroxymethylglutaryl-CoA reductase (Hmg1) genes contribute to resistance, with Hmg1 mutations showing site-specific resistance patterns.
Area of Science:
- Mycology
- Antifungal Resistance
- Molecular Biology
Background:
- Increasing prevalence of triazole-resistant Aspergillus fumigatus poses a global health threat.
- Resistance is often linked to mutations in the Cyp51A gene.
- Emerging evidence suggests other genes, like Hmg1, also contribute to resistance.
Purpose of the Study:
- To investigate the combined contribution of Cyp51A and Hmg1 mutations to atypical triazole resistance in Aspergillus fumigatus.
- To characterize the role of Hmg1 mutations in conferring triazole resistance.
- To understand the impact of mutation sites on resistance patterns.
Main Methods:
- Analysis of cyp51A and hmg1 gene sequences in clinical triazole-resistant Aspergillus fumigatus strains from Japan.
- Utilized CRISPR/Cas9 gene editing to replace mutant hmg1 alleles with wild-type alleles in clinical strains.
- Phenotypic evaluation of triazole susceptibility in modified strains.
Main Results:
- The combination of Cyp51A and Hmg1 mutations additively increases triazole resistance in Aspergillus fumigatus.
- Hmg1 mutations confer triazole resistance with patterns that vary depending on the specific mutation site.
- The contribution of Hmg1 to resistance is independent of Cyp51A mutations.
Conclusions:
- Both Cyp51A and Hmg1 mutations are critical components of the triazole resistance mechanism in Aspergillus fumigatus.
- Understanding the contribution of multiple genes, including Hmg1, is essential for a comprehensive view of antifungal resistance.
- Targeting Hmg1 or understanding its mutation-specific effects may offer new strategies against resistant fungal infections.
