Xiu Qian, Yin Xiaoru, Chen Yuanyuan, Zhang Ziyang, Mao Yushuai, Wang Tianshi, Zhang Jie, Zhou Mingguo, Duan Yabing
State Key Laboratory of Agricultural and Forestry Biosecurity, College of Plant Protection, Nanjing Agricultural University, Nanjing, China.
College of Science, Nanjing Agricultural University, Nanjing, China.
Elife. 2025 Aug 20;14:RP105892. doi: 10.7554/eLife.105892.
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 and . Additionally, the deletion of 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 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.
现代杀菌剂对作物病害管理做出了重大贡献，但抗性真菌菌株的出现导致其在病害防治中失效。因此，开发具有新型作用机制的杀菌剂是应对抗性的最有效措施。喹菌酮是一种新型喹啉类杀菌剂，对植物病原菌表现出卓越的抗真菌活性。然而，目前尚无关于其作用机制的可用信息。在此，我们利用转录组和代谢组分析观察嘧啶生物合成途径（PBP）中差异表达基因（DEGs）和差异积累代谢物（DAMs）的共富集模式，确定二氢乳清酸脱氢酶（DHODH）表达下调。外源性单磷酸尿苷（UMP）、尿苷或尿嘧啶（PBP中的代谢物）成功恢复了喹菌酮在[具体物种1]和[具体物种2]中对菌丝生长的抑制作用。此外，[基因名称]的缺失被确定是致死性的；然而，通过添加UMP、尿苷或尿嘧啶可以恢复ΔFgDHODHII突变体的菌丝生长。这些发现表明，[基因名称]的缺陷在功能上等同于喹菌酮对其活性的完全抑制。最后，分子对接、表面等离子体共振（SPR）和微量热泳动（MST）结果有力地支持了喹菌酮与FgDHODHII之间的精确相互作用。总的来说，这些发现为从头合成尿嘧啶作为喹菌酮的作用机制提供了有力证据，同时确定FgDHODHII为其特定靶点。
