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首页> 外文期刊>Applied Microbiology >Impact of Recently Emerged Sterol 14α-Demethylase (CYP51) Variants of Mycosphaerella graminicola on Azole Fungicide Sensitivity
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Impact of Recently Emerged Sterol 14α-Demethylase (CYP51) Variants of Mycosphaerella graminicola on Azole Fungicide Sensitivity

机译：最近出现的固醇14α-去甲基化酶（CYP51）变种对细支气单胞菌对偶氮杀真菌剂敏感性的影响

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The progressive decline in the effectiveness of some azole fungicides in controlling Mycosphaerella graminicola , causal agent of the damaging Septoria leaf blotch disease of wheat, has been correlated with the selection and spread in the pathogen population of specific mutations in the M. graminicola CYP51 ( MgCYP51 ) gene encoding the azole target sterol 14α-demethylase. Recent studies have suggested that the emergence of novel MgCYP51 variants, often harboring substitution S524T, has contributed to a decrease in the efficacy of prothioconazole and epoxiconazole, the two currently most effective azole fungicides against M. graminicola . In this study, we establish which amino acid alterations in novel MgCYP51 variants have the greatest impact on azole sensitivity and protein function. We introduced individual and combinations of identified alterations by site-directed mutagenesis and functionally determined their impact on azole sensitivity by expression in a Saccharomyces cerevisiae mutant YUG37:: erg11 carrying a regulatable promoter controlling native CYP51 expression. We demonstrate that substitution S524T confers decreased sensitivity to all azoles when introduced alone or in combination with Y461S. In addition, S524T restores the function in S. cerevisiae of MgCYP51 variants carrying the otherwise lethal alterations Y137F and V136A. Sensitivity tests of S. cerevisiae transformants expressing recently emerged MgCYP51 variants carrying combinations of alterations D134G, V136A, Y461S, and S524T reveal a substantial impact on sensitivity to the currently most widely used azoles, including epoxiconazole and prothioconazole. Finally, we exploit a recently developed model of the MgCYP51 protein to predict that the substantial structural changes caused by these novel combinations reduce azole interactions with critical residues in the binding cavity, thereby causing resistance.
机译：某些唑类杀真菌剂控制麦芽孢霉（Mycosphaerella graminicola）（小麦破坏性Septoria叶斑病的病原体）的有效性的逐渐下降与麦芽孢霉CYP51（MgCYP51）中特定突变的选择和传播有关）编码唑靶固醇14α-脱甲基酶的基因。最近的研究表明，经常带有取代S524T的新型MgCYP51变体的出现，导致降低了Prothioconazole和epoxiconazole的功效，Prothioconazole和epoxiconazole是目前最有效的两种杀真菌剂，用于抗M. graminicola。在这项研究中，我们确定了新型MgCYP51变体中的哪些氨基酸改变对唑敏感性和蛋白质功能有最大影响。我们通过定点诱变引入了识别的变化的个体和组合，并通过携带酿酒酵母突变体YUG37 :: erg11的表达来确定其对吡咯敏感性的影响，该突变体携带可调控的天然CYP51表达的启动子。我们证明，当单独或与Y461S结合引入时，取代S524T赋予对所有唑的敏感性降低。另外，S524T恢复携带否则致命的改变Y137F和V136A的MgCYP51变体在酿酒酵母中的功能。对表达最近出现的MgCYP51变体并带有D134G，V136A，Y461S和S524T变体组合的啤酒酵母转化子的敏感性测试表明，它们对目前最广泛使用的唑类化合物（包括环氧环唑和原硫代康唑）的敏感性产生重大影响。最后，我们利用MgCYP51蛋白的最新开发模型来预测由这些新颖组合引起的实质性结构变化会减少吡咯与结合腔中的关键残基的相互作用，从而引起耐药性。

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