Wheat pathogenZymoseptoria tritici N-myristoyltransferase inhibitors: on-target antifungal activity and an unusual metabolic defense mechanism

Abstract

<jats:title>ABSTRACT</jats:title><jats:p><jats:italic>Zymoseptoria tritici</jats:italic> is the causative agent of <jats:italic>Septoria tritici</jats:italic> 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 <jats:italic>Z. tritici</jats:italic> via inhibition of <jats:italic>N</jats:italic>-myristoyltransferase (NMT). We characterize <jats:italic>Z. tritici</jats:italic> NMT biochemically for the first time, profile the <jats:italic>in vivo Z. tritici</jats:italic> myristoylated proteome and identify and validate the first <jats:italic>Z. tritici</jats:italic> NMT inhibitors. Proteomic investigation of the downstream effects of NMT inhibition identified an unusual and novel mechanism of defense against chemical toxicity in <jats:italic>Z. tritici</jats:italic> through the application of comparative bioinformatics to deconvolute function from the previously largely unannotated <jats:italic>Z. tritici</jats:italic> 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 <jats:italic>Z. tritici</jats:italic>.</jats:p>