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

ABSTRACT: 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.

SUBMITTER: Fedoryshchak RO

PROVIDER: S-EPMC8341946 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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

Fedoryshchak Roman O RO Ocasio Cory A CA Strutton Benjamin B Mattocks Jo J Corran Andrew J AJ Tate Edward W EW

RSC chemical biology 20200513 2

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 w ...[more]

PMID: 34458749

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Project description:BackgroundThe fungal pathogen Zymoseptoria tritici is a significant constraint to wheat production in temperate cropping regions around the world. Despite its agronomic impacts, the mechanisms allowing the pathogen to asymptomatically invade and grow in the apoplast of wheat leaves before causing extensive host cell death remain elusive. Given recent evidence of extracellular vesicles (EVs)-secreted, membrane-bound nanoparticles containing molecular cargo-being implicated in extracellular communication between plants and fungal pathogen, we have initiated an in vitro investigation of EVs from this apoplastic fungal wheat pathogen. We aimed to isolate EVs from Z. tritici broth cultures and examine their protein composition in relation to the soluble protein in the culture filtrate and to existing fungal EV proteomes.ResultsZymoseptoria tritici EVs were isolated from broth culture filtrates using differential ultracentrifugation (DUC) and examined with transmission electron microscopy (TEM) and nanoparticle tracking analysis (NTA). Z. tritici EVs were observed as a heterogeneous population of particles, with most between 50 and 250 nm. These particles were found in abundance in the culture filtrates of viable Z. tritici cultures, but not heat-killed cultures incubated for an equivalent time and of comparable biomass. Bottom-up proteomic analysis using LC-MS/MS, followed by stringent filtering revealed 240 Z. tritici EV proteins. These proteins were distinct from soluble proteins identified in Z. tritici culture filtrates, but were similar to proteins identified in EVs from other fungi, based on sequence similarity analyses. Notably, a putative marker protein recently identified in Candida albicans EVs was also consistently detected in Z. tritici EVs.ConclusionWe have shown EVs can be isolated from the devastating fungal wheat pathogen Z. tritici and are similar to protein composition to previously characterised fungal EVs. EVs from human pathogenic fungi are implicated in virulence, but the role of EVs in the interaction of phytopathogenic fungi and their hosts is unknown. These in vitro analyses provide a basis for expanding investigations of Z. tritici EVs in planta, to examine their involvement in the infection process of this apoplastic wheat pathogen and more broadly, advance understanding of noncanonical secretion in filamentous plant pathogens.

Project description:BackgroundThe ascomycete fungus Zymoseptoria tritici (synonyms: Mycosphaerella graminicola, Septoria tritici) is a major pathogen of wheat that causes the economically important foliar disease Septoria tritici blotch. Despite its importance as a pathogen, little is known about the reaction of this fungus to light. To test for light responses, cultures of Z. tritici were grown in vitro for 16-h days under white, blue or red light, and their transcriptomes were compared with each other and to those obtained from control cultures grown in darkness.ResultsThere were major differences in gene expression with over 3400 genes upregulated in one or more of the light conditions compared to dark, and from 1909 to 2573 genes specifically upregulated in the dark compared to the individual light treatments. Differences between light treatments were lower, ranging from only 79 differentially expressed genes in the red versus blue comparison to 585 between white light and red. Many of the differentially expressed genes had no functional annotations. For those that did, analysis of the Gene Ontology (GO) terms showed that those related to metabolism were enriched in all three light treatments, while those related to growth and communication were more prevalent in the dark. Interestingly, genes for effectors that have been shown previously to be involved in pathogenicity also were upregulated in one or more of the light treatments, suggesting a possible role of light for infection.ConclusionsThis analysis shows that Z. tritici can sense and respond to light with a huge effect on transcript abundance. High proportions of differentially expressed genes with no functional annotations illuminates the huge gap in our understanding of light responses in this fungus. Differential expression of genes for effectors indicates that light could be important for pathogenicity; unknown effectors may show a similar pattern of transcription. A better understanding of the effects of light on pathogenicity and other biological processes of Z. tritici could help to manage Septoria tritici blotch in the future.

Dataset Information

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

Publications

Wheat pathogen <i>Zymoseptoria tritici N</i>-myristoyltransferase inhibitors: on-target antifungal activity and an unusual metabolic defense mechanism.

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