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Cited by 1Fungal Plant Pathogen ControlAntifungal resistance and susceptibilityBiochemical and Molecular Research

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Action mechanism of a novel agrichemical quinofumelin against Fusarium graminearum

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Xiu, Qian, Yin, Xiaoru, Chen, Yuanyuan, Zhang, Ziyang, Mao, Yushuai, Wang, Tianshi, Zhang, Jie, Zhou, Mingguo, Duan, Yabing·2025·eLife
DOI 10.7554/elife.105892PMC PMC12367298

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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 uridine monophosphate (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 a mechanism of action for quinofumelin while identifying FgDHODHII as its specific target.

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Figure 1. Analysis of transcriptome sequencing data in F.graminearum PH-1 treated with quinofumelin. (A) Bar chart illustrating the comparison of differentially expressed genes between EC90 treatments and the control. (B) Volcano plot depicting up-regulated differentially expressed genes (DEGs) as red scattered dots and down-regulated DEGs as blue scattered dots. (C) Cluster heat maps displaying gene relative expression values using RNA-seq data scale-standardized values. (D) Bubble map presenting the results of Gene Ontology (GO) enrichment analysis for DEGs. (E) Bubble map showcasing the findings of Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis for DEGs.
Figure 1. Analysis of transcriptome sequencing data in F.graminearum PH-1 treated with quinofumelin. (A) Bar chart illustrating the comparison of differentially expressed genes between EC90 treatments and the control. (B) Volcano plot depicting up-regulated differentially expressed genes (DEGs) as red scattered dots and down-regulated DEGs as blue scattered dots. (C) Cluster heat maps displaying gene relative expression values using RNA-seq data scale-standardized values. (D) Bubble map presenting the results of Gene Ontology (GO) enrichment analysis for DEGs. (E) Bubble map showcasing the findings of Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis for DEGs.CC BY · PubMed Central
Figure 1—figure supplement 1. Principal component analysis plots between the experimental (EC90: 1 μg/mL quinofumelin) and control (CK) samples.
Figure 1—figure supplement 1. Principal component analysis plots between the experimental (EC90: 1 μg/mL quinofumelin) and control (CK) samples.CC BY · PubMed Central
Figure 1—figure supplement 2. Cluster analysis of the metabolite group. (A) 3D principal component analysis diagram of EC90, CK, and QC samples in positive ion mode. (B) 3D principal component analysis diagram of EC90, CK, and QC samples in negative ion mode. (C) Heat map of inter-sample correlation analysis in positive ion mode. (D) Heat map of inter-sample correlation analysis in negative ion mode.
Figure 1—figure supplement 2. Cluster analysis of the metabolite group. (A) 3D principal component analysis diagram of EC90, CK, and QC samples in positive ion mode. (B) 3D principal component analysis diagram of EC90, CK, and QC samples in negative ion mode. (C) Heat map of inter-sample correlation analysis in positive ion mode. (D) Heat map of inter-sample correlation analysis in negative ion mode.CC BY · PubMed Central
Figure 2. Difference analysis and enrichment analysis of metabolome data in F. graminearum PH-1 treated with quinofumelin. (A) Bar chart illustrating the number of differential accumulation metabolites (DAMs) quantity in experimental groups (EC90) and control groups (CK) in positive ion mode. (B) Volcanic map of all metabolites in positive ion mode. The red scatter points represent up-regulated DAMs, while the blue scatter points represent down-regulated DAMs. (C) Classification and proportion of DAMs. (D) Bubble diagram of differential accumulation metabolite Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment pathway. (E) Pyrimidine de novo biosynthesis pathway in Fusarium graminearum. The left box plots represent the relative content of eight metabolite samples, while the right box represents the relative content of six gene samples. The color gradient from navy blue to firebrick red indicates a progression from low to high content.
Figure 2. Difference analysis and enrichment analysis of metabolome data in F. graminearum PH-1 treated with quinofumelin. (A) Bar chart illustrating the number of differential accumulation metabolites (DAMs) quantity in experimental groups (EC90) and control groups (CK) in positive ion mode. (B) Volcanic map of all metabolites in positive ion mode. The red scatter points represent up-regulated DAMs, while the blue scatter points represent down-regulated DAMs. (C) Classification and proportion of DAMs. (D) Bubble diagram of differential accumulation metabolite Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment pathway. (E) Pyrimidine de novo biosynthesis pathway in Fusarium graminearum. The left box plots represent the relative content of eight metabolite samples, while the right box represents the relative content of six gene samples. The color gradient from navy blue to firebrick red indicates a progression from low to high content.CC BY · PubMed Central
Figure 2—figure supplement 1. Difference analysis of metabolic group data. (A) A bar chart illustrating the number of differentially accumulated metabolite (DAM) quantity in experimental group (EC90) and control group (CK) in the negative ion mode. (B) Volcanic map of all metabolites in the negative ion mode. The red scatter points represent the up-regulated DAMs, and the blue scatter points represent the down-regulated DAMs. (C) Pie diagram of differential metabolite enrichment pathway classification.
Figure 2—figure supplement 1. Difference analysis of metabolic group data. (A) A bar chart illustrating the number of differentially accumulated metabolite (DAM) quantity in experimental group (EC90) and control group (CK) in the negative ion mode. (B) Volcanic map of all metabolites in the negative ion mode. The red scatter points represent the up-regulated DAMs, and the blue scatter points represent the down-regulated DAMs. (C) Pie diagram of differential metabolite enrichment pathway classification.CC BY · PubMed Central
Figure 2—figure supplement 2. DHODHII gene expression in F. graminearum is affected by quinofumelin. After the strain PH-1 was cultured in Yeast extract peptone dextrose (YEPD) medium for 36 hr, the EC50 (0.035 μg/mL) and EC90 (1 μg/mL) of quinofumelin were added, respectively, followed by an additional 12 hr incubation period. The expression level of the DHODHII gene was subsequently quantified using RT-qPCR. Data represent the mean values and standard errors derived from three independent replicates. Letters above the columns indicate statistically significant differences among treatments (p<0.05, ANOVA, LSD).
Figure 2—figure supplement 2. DHODHII gene expression in F. graminearum is affected by quinofumelin. After the strain PH-1 was cultured in Yeast extract peptone dextrose (YEPD) medium for 36 hr, the EC50 (0.035 μg/mL) and EC90 (1 μg/mL) of quinofumelin were added, respectively, followed by an additional 12 hr incubation period. The expression level of the DHODHII gene was subsequently quantified using RT-qPCR. Data represent the mean values and standard errors derived from three independent replicates. Letters above the columns indicate statistically significant differences among treatments (p<0.05, ANOVA, LSD).CC BY · PubMed Central
Figure 3. Phylogenetic tree of DHODHII proteins. The phylogenetic tree was constructed based on the amino acid sequences of DHODHII homologous proteins with Mega X using the neighbor-joining method. The bootstrap values from 1000 replications are indicated on the branches. Motif pattern information was generated using the MEME suite12, while functional domain information and protein coordinates were obtained through CD-search. The final phylogenetic tree was visualized using TBtools. FgDHODHII was highlighted in red. The amino acid sequence of DHODHII from Alternaria alternata (AA0117_g542), Aspergillus nidulans (ANIA_05909), Aspergillus oryzae (AO1008_05965), Blumeria graminis (BLGH_00861), Botrytis cinerea (Bcin15g04150), Botrytis elliptica (BELL_0162g00150), Colletotrichum asianum (GQ607_007053), Colletotrichum fioriniae (CFIO01_03831), Colletotrichum higginsianum (CH063_10143), Corynespora cassiicola (BS50DRAFT_576390), Erysiphe necator (EV44_g2092), Erysiphe pulchra (EPUL_004094), Fusarium euwallaceae (BHE90_002825), Fusarium floridanum (CEP51_012005), Fusarium fujikuroi (FFMR_05040), Fusarium graminearum (FGSG_09678), Fusarium nygamai (FNYG_10990), Fusarium odoratissimum (FOIG_08270), Fusarium oxysporum (FOXG_08390), Fusarium pseudograminearum (FPSE_04283), Fusarium solani (NechaG15121), Fusarium verticillioides (FVEG_06288), Magnaporthe oryzae (MGG_08814), Neurospora crassa (NCU06532), Oidium neolycopersici (OnM2_089032), Pestalotiopsis fici (PFICI_04984), Podospora anserina (PODANS_6_7920), Puccinia graminis (PGTG_16739), Puccinia triticina (PTTG_02070), Rhizoctonia solani (RSOLAG22IIIB_08327), Schizosaccharomyces pombe (SPAC57A10.12c), Ustilaginoidea virens (UVI_02052880), Verticillium alfalfae (VDBG_01322), Verticillium dahliae (VDAG_07935), and Zymoseptoria tritici (Mycgr3G72548) were accessed in EnsemblFungi database.
Figure 3. Phylogenetic tree of DHODHII proteins. The phylogenetic tree was constructed based on the amino acid sequences of DHODHII homologous proteins with Mega X using the neighbor-joining method. The bootstrap values from 1000 replications are indicated on the branches. Motif pattern information was generated using the MEME suite12, while functional domain information and protein coordinates were obtained through CD-search. The final phylogenetic tree was visualized using TBtools. FgDHODHII was highlighted in red. The amino acid sequence of DHODHII from Alternaria alternata (AA0117_g542), Aspergillus nidulans (ANIA_05909), Aspergillus oryzae (AO1008_05965), Blumeria graminis (BLGH_00861), Botrytis cinerea (Bcin15g04150), Botrytis elliptica (BELL_0162g00150), Colletotrichum asianum (GQ607_007053), Colletotrichum fioriniae (CFIO01_03831), Colletotrichum higginsianum (CH063_10143), Corynespora cassiicola (BS50DRAFT_576390), Erysiphe necator (EV44_g2092), Erysiphe pulchra (EPUL_004094), Fusarium euwallaceae (BHE90_002825), Fusarium floridanum (CEP51_012005), Fusarium fujikuroi (FFMR_05040), Fusarium graminearum (FGSG_09678), Fusarium nygamai (FNYG_10990), Fusarium odoratissimum (FOIG_08270), Fusarium oxysporum (FOXG_08390), Fusarium pseudograminearum (FPSE_04283), Fusarium solani (NechaG15121), Fusarium verticillioides (FVEG_06288), Magnaporthe oryzae (MGG_08814), Neurospora crassa (NCU06532), Oidium neolycopersici (OnM2_089032), Pestalotiopsis fici (PFICI_04984), Podospora anserina (PODANS_6_7920), Puccinia graminis (PGTG_16739), Puccinia triticina (PTTG_02070), Rhizoctonia solani (RSOLAG22IIIB_08327), Schizosaccharomyces pombe (SPAC57A10.12c), Ustilaginoidea virens (UVI_02052880), Verticillium alfalfae (VDBG_01322), Verticillium dahliae (VDAG_07935), and Zymoseptoria tritici (Mycgr3G72548) were accessed in EnsemblFungi database.CC BY · PubMed Central
Figure 4. Recovery test of mycelial growth suppressed by quinofumelin. All strains were incubated on Czapek Solution Agar (CZA) plates at 25°C for 3 days. F. graminearum strains PH-1, 512E-8, SX2117, XY-4, and R10. The left image shows the colony morphology, while the right image is a bar chart of colony diameters.
Figure 4. Recovery test of mycelial growth suppressed by quinofumelin. All strains were incubated on Czapek Solution Agar (CZA) plates at 25°C for 3 days. F. graminearum strains PH-1, 512E-8, SX2117, XY-4, and R10. The left image shows the colony morphology, while the right image is a bar chart of colony diameters.CC BY · PubMed Central
Figure 4—figure supplement 1. Recovery test of mycelial growth suppressed by quinofumelin. All strains were incubated on Czapek Solution Agar (CZA) plates at 25°C for 3 days. F. asiaticum strains: 2021, HAC2105, 512 F-10, 512 F-2, and 512 F-6. The left image shows the colony morphology, while the right image is a bar chart of colony diameters.
Figure 4—figure supplement 1. Recovery test of mycelial growth suppressed by quinofumelin. All strains were incubated on Czapek Solution Agar (CZA) plates at 25°C for 3 days. F. asiaticum strains: 2021, HAC2105, 512 F-10, 512 F-2, and 512 F-6. The left image shows the colony morphology, while the right image is a bar chart of colony diameters.CC BY · PubMed Central
Figure 5. Mycelial growth of FgDHODHII deletion mutants on Czapek Solution Agar (CZA) plates. (A) Mycelial growth of the FgDHODHII deletion mutants and the parental strain was observed in the presence or absence of 50 μg/mL uridine. (B) Recovery of mycelial growth of the FgDHODHII deletion mutants was observed in the presence of 50 μg/mL dihydroorotate, uridine monophosphate (UMP), uridine, or uracil. All strains were incubated at 25°C for 3 days.
Figure 5. Mycelial growth of FgDHODHII deletion mutants on Czapek Solution Agar (CZA) plates. (A) Mycelial growth of the FgDHODHII deletion mutants and the parental strain was observed in the presence or absence of 50 μg/mL uridine. (B) Recovery of mycelial growth of the FgDHODHII deletion mutants was observed in the presence of 50 μg/mL dihydroorotate, uridine monophosphate (UMP), uridine, or uracil. All strains were incubated at 25°C for 3 days.CC BY · PubMed Central
Figure 6. Validation and analysis of quinofumelin’s binding affinity to FgDHODHII. (A) Three-dimensional model of the wild-type FgDHODHII are depicted, with an enlarged view highlighting the binding site for quinofumelin on the corresponding FgDHODHII models. (B) The surface plasmon resonance (SPR) response (RU) analysis and fitting results demonstrate the interaction between quinofumelin and FgDHODHII. (C) Microscale thermophoresis (MST) analysis to detect the binding of quinofumelin and FgDHODHII.
Figure 6. Validation and analysis of quinofumelin’s binding affinity to FgDHODHII. (A) Three-dimensional model of the wild-type FgDHODHII are depicted, with an enlarged view highlighting the binding site for quinofumelin on the corresponding FgDHODHII models. (B) The surface plasmon resonance (SPR) response (RU) analysis and fitting results demonstrate the interaction between quinofumelin and FgDHODHII. (C) Microscale thermophoresis (MST) analysis to detect the binding of quinofumelin and FgDHODHII.CC BY · PubMed Central
Figure 6—figure supplement 1. SDS-PAGE electrophoresis of the fusion protein. (A) The purification effect of pCold-9 ×His-MBP-TEV-DHODHII. (B) The purification effect of pET-28a (+)-DHODHII. (C) The purification of pET-28a (+) -DHODHII124-467. The lane M is a protein marker; in a and c, lanes 1–8 were supernatant, precipitate, flow through solution, and eluent containing 5, 20, 50, 100, and 250 mM imidazole, respectively. In b, lanes 1–9 were the whole fungus, supernatant, precipitate, flow-through solution, and eluent containing 5, 20, 50, 100, and 250 mM imidazole.
Figure 6—figure supplement 1. SDS-PAGE electrophoresis of the fusion protein. (A) The purification effect of pCold-9 ×His-MBP-TEV-DHODHII. (B) The purification effect of pET-28a (+)-DHODHII. (C) The purification of pET-28a (+) -DHODHII124-467. The lane M is a protein marker; in a and c, lanes 1–8 were supernatant, precipitate, flow through solution, and eluent containing 5, 20, 50, 100, and 250 mM imidazole, respectively. In b, lanes 1–9 were the whole fungus, supernatant, precipitate, flow-through solution, and eluent containing 5, 20, 50, 100, and 250 mM imidazole.CC BY · PubMed Central
Figure 7. A model of the pyrimidine pathway that quinofumelin attacks.
Figure 7. A model of the pyrimidine pathway that quinofumelin attacks.CC BY · PubMed Central

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Metadata

Authors
Xiu, Q., Yin, X., Chen, Y., Zhang, Z., Mao, Y., Wang, T., Zhang, J., Zhou, M., & Duan, Y.
Affiliations
Nanjing Agricultural University (CN)
Corresponding author
  • Zhou, Mingguo
  • Duan, Yabing
ORCID
Venue
eLife
Publisher
eLife Sciences Publications, Ltd
Published
2025-08-20
Volume
14
ISSN
2050-084X (ISSN-L)
DOI
10.7554/elife.105892
PMC
PMC12367298
OpenAlex
W4408224334
Cited by
1
References
44
Citations by year
2026: 1
Type
posted content
Language
en
Open access
Licence
Locations
  • eLife (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Key Research and Development Program of China (2022YFD1400100)
  • National Natural Science Foundation of China (32072448)
Topics
  • Life Sciences › Agricultural and Biological Sciences › Plant Science › Fungal Plant Pathogen Control
  • Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Molecular Research
Keywords
Fusarium graminearum, Fusarium asiaticum, mechanism of action, dihydroorotate dehydrogenase, pyrimidine synthesis, uracil biosynthesis, uridine monophosphate, fungicide resistance, antifungal activity, mycelial growth inhibition, molecular docking, binding affinity
MeSH terms
Dihydroorotate Dehydrogenase, Antifungal Agents, Fungal Proteins, Fungicides, Industrial, Fusarium, Quinolines, Uridine, Gene Expression Regulation, Fungal, Gene Expression Profiling

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Xiu, Q., Yin, X., Chen, Y., Zhang, Z., Mao, Y., Wang, T., Zhang, J., Zhou, M., & Duan, Y. (2025). Action mechanism of a novel agrichemical quinofumelin against Fusarium graminearum. eLife. https://doi.org/10.7554/elife.105892

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