Wheat pathogen Zymoseptoria tritici N-myristoyltransferase inhibitors: on-target antifungal activity and an unusual metabolic defense mechanism,RSC Chemical Biology

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Wheat pathogen Zymoseptoria tritici N-myristoyltransferase inhibitors: on-target antifungal activity and an unusual metabolic defense mechanism
RSC Chemical Biology ( IF 4.2 ) Pub Date : 2020-05-13 , DOI: 10.1039/d0cb00020e
Roman O Fedoryshchak _{1,

2} , Cory A Ocasio ₂ , Benjamin Strutton ₃ , Jo Mattocks ₃ , Andrew J Corran ₃ , Edward W Tate _{1,

2}

Affiliation

Zymoseptoria tritici is the causative agent of Septoria tritici blotch (STB), which costs billions of dollars annually to major wheat-producing countries in terms of both fungicide use and crop loss. Agricultural pathogenic fungi have acquired resistance to most commercially available fungicide classes, and the rate of discovery and development of new fungicides has stalled, demanding new approaches and insights. Here we investigate a potential mechanism of targeting an important wheat pathogen Z. tritici via inhibition of N-myristoyltransferase (NMT). We characterize Z. tritici NMT biochemically for the first time, profile the in vivo Z. tritici myristoylated proteome and identify and validate the first Z. tritici NMT inhibitors. Proteomic investigation of the downstream effects of NMT inhibition identified an unusual and novel mechanism of defense against chemical toxicity in Z. tritici through the application of comparative bioinformatics to deconvolute function from the previously largely unannotated Z. tritici proteome. Research into novel fungicidal modes-of-action is essential to satisfy an urgent unmet need for novel fungicide targets, and we anticipate that this study will serve as a useful proteomics and bioinformatics resource for researchers studying Z. tritici.

中文翻译：

小麦病原体小麦发酵斑孢 N-肉豆蔻酰基转移酶抑制剂：靶向抗真菌活性和不寻常的代谢防御机制

小麦发酵腐霉是小麦斑枯病 (STB) 的病原体，该病每年给主要小麦生产国造成数十亿美元的损失，包括杀菌剂的使用和作物损失。农业病原真菌已经对大多数市售杀菌剂类别产生了抗药性，并且新杀菌剂的发现和开发速度已经停滞，需要新的方法和见解。在这里，我们研究了通过抑制N -肉豆蔻酰转移酶（NMT）来靶向重要的小麦病原体小麦病菌的潜在机制。我们首次对小麦小麦NMT 进行了生化表征，分析了体内小麦小麦豆蔻酰化蛋白质组，并鉴定和验证了第一个小麦小麦NMT 抑制剂。通过应用比较生物信息学对先前基本上未注释的小麦小麦蛋白质组进行解卷积功能，对 NMT 抑制下游效应的蛋白质组学研究发现了小麦小麦中一种不寻常且新颖的防御化学毒性的机制。对新型杀菌剂作用模式的研究对于满足对新型杀菌剂靶标的迫切未满足的需求至关重要，我们预计这项研究将为研究小麦小麦的研究人员提供有用的蛋白质组学和生物信息学资源。

更新日期：2020-05-13

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