Action mechanism of a novel agrichemical quinofumelin against Fusarium graminearum
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Curated by eLife
eLife Assessment
In this valuable study, the authors show the physiological response and molecular pathway mediating the effect of quinofumelin, a developed fungicide with an unknown mechanism. The authors present convincing data suggesting the involvement of the uridine/uracil biosynthesis pathway, by combining in vivo microbiology characterization as well as in vitro biochemical binding results.
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Abstract
Modern fungicides have made significant contributions to crop disease management, but the development of resistant fungal strains has caused their failure in disease control. Therefore, developing fungicides with novel action mechanisms is the most effective measure to manage resistance. Quinofumelin, a novel quinoline fungicide, exhibits exceptional antifungal activity against phytopathogens. However, there is currently no available information on its mechanism of action. Here, we used transcriptome and metabolome analysis to observe a co-enrichment pattern of differentially expressed genes (DEGs) and differentially accumulated metabolites (DAMs) within pyrimidine biosynthesis pathway (PBP), identifying down-regulation of dihydroorotate dehydrogenase (DHODH). Exogenous UMP, uridine or uracil (metabolites in PBP) successfully restored quinofumelin-induced inhibition of mycelial growth in Fusarium graminearum and Fusarium asiaticum . Additionally, the deletion of FgDHODHII was determined to be lethal; however, mycelial growth of ΔFgDHODHII mutants could be restored by adding UMP, uridine or uracil. These findings indicate that the deficiencies in FgDHODHII are functionally equivalent to complete inhibition of its activity by quinofumelin. Finally, molecular docking, surface plasmon resonance (SPR) and microscale thermophoresis (MST) results strongly support the precise interaction between quinofumelin and FgDHODHII. Collectively, these findings provide compelling evidence for the involvement of de novo uracil biosynthesis as mechanism of action for quinofumelin while identifying FgDHODHII as its specific target.
Article activity feed
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eLife Assessment
In this valuable study, the authors show the physiological response and molecular pathway mediating the effect of quinofumelin, a developed fungicide with an unknown mechanism. The authors present convincing data suggesting the involvement of the uridine/uracil biosynthesis pathway, by combining in vivo microbiology characterization as well as in vitro biochemical binding results.
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Reviewer #1 (Public review):
Summary:
Phytophathogens including fungal pathogens such as F. graminearum remain a major threat to agriculture and food security. Several agriculturally relevant fungicides including the potent Quinofumelin have been discovered to date, yet the mechanisms of their action and specific targets within the cell remain unclear. This paper sets out to contribute to addressing these outstanding questions.
Strengths:
The paper is generally well-written and provides convincing data to support their claims for the impact of Quinofumelin on fungal growth, the target of the drug, and the potential mechanism. Critically the authors identify an important pyrimidine pathway dihydroorotate dehydrogenase (DHODH) gene FgDHODHII in the pathway or mechanism of the drug from the prominent plant pathogen F. graminearum, …
Reviewer #1 (Public review):
Summary:
Phytophathogens including fungal pathogens such as F. graminearum remain a major threat to agriculture and food security. Several agriculturally relevant fungicides including the potent Quinofumelin have been discovered to date, yet the mechanisms of their action and specific targets within the cell remain unclear. This paper sets out to contribute to addressing these outstanding questions.
Strengths:
The paper is generally well-written and provides convincing data to support their claims for the impact of Quinofumelin on fungal growth, the target of the drug, and the potential mechanism. Critically the authors identify an important pyrimidine pathway dihydroorotate dehydrogenase (DHODH) gene FgDHODHII in the pathway or mechanism of the drug from the prominent plant pathogen F. graminearum, confirming it as the target for Quinofumelin. The evidence is supported by transcriptomic, metabolomic as well as MST, SPR, molecular docking/structural biology analyses.
Weaknesses:
Whilst the study adds to our knowledge about this drug, it is, however, worth stating that previous reports (although in different organisms) by Higashimura et al., 2022 https://pmc.ncbi.nlm.nih.gov/articles/PMC9716045/ had already identified DHODH as the target for Quinofumelin and hence this knowledge is not new and hence the authors may want to tone down the claim that they discovered this mechanism and also give sufficient credit to the previous authors work at the start of the write-up in the introduction section rather than in passing as they did with reference 25? other specific recommendations to improve the text are provided in the recommendations for authors section below.
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Reviewer #2 (Public review):
Summary:
In the current study, the authors aim to identify the mode of action/molecular mechanism of characterized a fungicide, quinofumelin, and its biological impact on transcriptomics and metabolomics in Fusarium graminearum and other Fusarium species. Two sets of data were generated between quinofumelin and no treatment group, and differentially abundant transcripts and metabolites were identified. The authors further focused on uridine/uracil biosynthesis pathway, considering the significant up- and down-regulation observed in final metabolites and some of the genes in the pathways. Using a deletion mutant of one of the genes and in vitro biochemical assays, the authors concluded that quinofumelin binds to the dihydroorotate dehydrogenase.
Strengths:
Omics datasets were leveraged to understand the …
Reviewer #2 (Public review):
Summary:
In the current study, the authors aim to identify the mode of action/molecular mechanism of characterized a fungicide, quinofumelin, and its biological impact on transcriptomics and metabolomics in Fusarium graminearum and other Fusarium species. Two sets of data were generated between quinofumelin and no treatment group, and differentially abundant transcripts and metabolites were identified. The authors further focused on uridine/uracil biosynthesis pathway, considering the significant up- and down-regulation observed in final metabolites and some of the genes in the pathways. Using a deletion mutant of one of the genes and in vitro biochemical assays, the authors concluded that quinofumelin binds to the dihydroorotate dehydrogenase.
Strengths:
Omics datasets were leveraged to understand the physiological impact of quinofumelin, showing the intracellular impact of the fungicide. The characterization of FgDHODHII deletion strains with supplemented metabolites clearly showed the impact of the enzyme on fungal growth.
Weaknesses:
Some interpretation of results is not accurate and some experiments lack controls. The comparison between quinofumelin-treated deletion strains, in the presence of different metabolites didn't suggest the fungicide is FgDHODHII specific. A wild type is required in this experiment.
Potential Impact: Confirming the target of quinofumelin may help understand its resistance mehchanism, and further development of other inhibitory molecules against the target.
The manuscript would benefit more in explaining the study rationale if more background on previous characterization of this fungicide on Fusarium is given.
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Reviewer #3 (Public review):
Summary:
The manuscript shows the mechanism of action of quinofumelin, a novel fungicide, against the fungus Fusarium graminearum. Through omics analysis, phenotypic analysis, and in silico approaches, the role of quinofumelin in targeting DHODH is uncovered.
Strengths:
The phenotypic analysis and mutant generation are nice data and add to the role of metabolites in bypassing pyrimidine biosynthesis.
Weaknesses:
The role of DHODH in this class of fungicides has been known and this data does not add any further significance to the field. The work of Higashimura et al is not appreciated well enough as they already showed the role of quinofumelin upon DHODH II.
There is no mention of the other fungicide within this class ipflufenoquin, as there is ample data on this molecule.
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