Metabolomics and Cheminformatics Analysis of Antifungal Function of Plant Metabolites

Abstract

Fusarium head blight (FHB), primarily caused by Fusarium graminearum, is a devastating disease of wheat. Partial resistance to FHB of several wheat cultivars includes specific metabolic responses to inoculation. Previously published studies have determined major metabolic changes induced by pathogens in resistant and susceptible plants. Functionality of the majority of these metabolites in resistance remains unknown. In this work we have made a compilation of all metabolites determined as selectively accumulated following FHB inoculation in resistant plants. Characteristics, as well as possible functions and targets of these metabolites, are investigated using cheminformatics approaches with focus on the likelihood of these metabolites acting as drug-like molecules against fungal pathogens. Results of computational analyses of binding properties of several representative metabolites to homology models of fungal proteins are presented. Theoretical analysis highlights the possibility for strong inhibitory activity of several metabolites against some major proteins in Fusarium graminearum, such as carbonic anhydrases and cytochrome P450s. Activity of several of these compounds has been experimentally confirmed in fungal growth inhibition assays. Analysis of anti-fungal properties of plant metabolites can lead to the development of more resistant wheat varieties while showing novel application of cheminformatics approaches in the analysis of plant/pathogen interactions.

Perspectives on the specific targeting of Fusarium graminearum for the development of alternative head blight treatment approaches

“…The monophenolic compound ferulic acid, the most abundant polyphenolic acid compound found in wheat grain, has been shown to function as an efficient inhibitor of type B trichothecene biosynthesis and Tri gene expression in Fg in liquid cultures (Boutigny et al ., , ; Ponts et al ., ). Ferulic acid also shows growth inhibitory activity against Fg in vitro (Cuperlovic‐Culf et al ., ). In addition biphenolic flavonoid compounds are also known to inhibit production of T‐2 toxin in F. sporotrichioides (Desjardins et al ., ).…”

“…In addition biphenolic flavonoid compounds are also known to inhibit production of T‐2 toxin in F. sporotrichioides (Desjardins et al ., ). Indeed, it has recently been shown that the flavonoid compound naringenin inhibits Fg growth in vitro (Cuperlovic‐Culf et al ., ). Further to this, oxidative stress created in liquid cultures of Fg by addition of oxidizing agents such as H 2 O 2 has been shown to cause strong induction of expression of several Tri genes and increased production of TCTB (Ponts et al ., , ).…”

“…Sequence comparison for these three genes in Fg with human and wheat CYP51 paralogues shows some sequence similarity; however, although active sites for CYP51 proteins are comparable between species, there are major sequence differences that can be used for the development of more specific drugs. Using metabolomics and cheminformatics approaches, several plant metabolites have recently been identified that might target fungal cytochrome P450s (Cuperlovic‐Culf et al ., ). However, these are yet to be validated as authentic inhibitors of CYP51 proteins.…”

“…Low pH combined with amines such as agmatine and putrescine leads to overexpression of Tri5 and increased DON production. In addition, several resistance‐related metabolites have been shown as potential inhibitors of CA function (Cuperlovic‐Culf et al ., ). The effect of inhibition of different CA isozymes in Fg and plants may provide an interesting avenue for further search for targeted antifungal agents with some recent developments reviewed by Lehneck & Pöggeler ().…”

Application of Metabolomic Analysis in Exploration of Plant Genetic Resources

“…In the analysed oat accessions, oxycinnamic, oxybenzoic, pipecolic and 5-hydroxypipecolic acids have been identified. Since the latter are known for their anti-Fusarium activity (Cuperlovic-Culf et al, 2016), it becomes possible to use collections for selecting accessions with the highest concentrations of these compounds as sources of potential resistance to Fusarium.…”