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.

中文翻译：

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烟曲霉 Hmg1 突变及其对三唑敏感性的贡献

耐三唑的烟曲霉是一个全球性的健康问题。一般来说，由 Cyp51A 的特定氨基酸取代引起的每种三唑抗性模式都有一个典型的模式，具体取决于突变位点。我们评估了 Cyp51A 和 Hmg1 突变对烟曲霉中非典型三唑耐药性的贡献。我们使用在日本收集的临床耐三唑烟曲霉菌株并研究了 cyp51A 和 hmg1 基因的序列。为了描述 hmg1 突变与非典型三唑耐药性之间的关联，临床多唑耐药菌株中的突变 hmg1 等位基因通过 CRISPR/Cas9 系统替换为野生型 hmg1 等位基因。在我们的研究中，Cyp51A 突变和 Hmg1 突变的组合显示对三唑耐药性有额外贡献。我们还证明了 Hmg1 突变赋予的三唑抗性根据突变位点显示出不同的模式，类似于 Cyp51A 突变。我们的结果表明，关注多个基因的表型对于阐明烟曲霉三唑抗性机制的总体情况至关重要。总结 耐三唑类烟曲霉的数量正在增加。我们证实真菌中羟甲基戊二酰辅酶A还原酶（Hmg1）的突变与Cyp51A突变不同，导致耐药性不同，并且易感模式因突变位点而异。我们的结果表明，关注多个基因的表型对于阐明烟曲霉三唑抗性机制的总体情况至关重要。总结 耐三唑类烟曲霉的数量正在增加。我们证实真菌中羟甲基戊二酰辅酶A还原酶（Hmg1）的突变与Cyp51A突变不同，导致耐药性不同，并且易感模式因突变位点而异。我们的结果表明，关注多个基因的表型对于阐明烟曲霉三唑抗性机制的总体情况至关重要。总结 耐三唑类烟曲霉的数量正在增加。我们证实真菌中羟甲基戊二酰辅酶A还原酶（Hmg1）的突变与Cyp51A突变不同，导致耐药性不同，并且易感模式因突变位点而异。