Ma Jun-Hao, Ying Mao-Xue, Lu Zong-Wei, Guan Ze-Wei, Zhang Chuan-Qing, Zhu Xiao-Lei, Yang Guang-Fu
State Key Laboratory of Green Pesticide, International Joint Research Center for Intelligent Biosensor Technology and Health, Central China Normal University, Wuhan 430079, PR China.
College of Advanced Agricultural Sciences, Zhejiang A and F University, Lin'an 311300, PR China.
Int J Biol Macromol. 2025 Mar;293:139360. doi: 10.1016/j.ijbiomac.2024.139360. Epub 2024 Dec 30.
Botrytis cinerea populations resistant to succinate dehydrogenase inhibitors (SDHIs) represent a major problem for the sustainable development of modern agriculture. In the present study, the resistance mechanism of B_P225F and B_H272R mutations in B. cinerea SDH (BcSDH) resistant to SDHIs fungicides, including boscalid (BOS), penflufen (PEN), pydiflumetofen (PYD), fluopyram (FLU), and benzovindiflupyr (BEN), was uncovered. The biological assay results showed that both mutations exhibited different resistant factor (RF) for SDHIs. The molecular modeling results indicated that the B_P225F and B_H272R mutations had great effects on the conformational change of the binding pocket and the binding modes of inhibitors. For both mutations, the cation-π interaction between ligand and the residue of C_R88, playing an important contribution to the binding affinity in wild type (WT), was decreased in B_P225F and disappeared in B_H272R. It was interesting that an additional hydrogen bond (Hbond) established between inhibitors with B_R272 compensated for the reduction in binding energy that occurred with the B_H272R mutation. As a result, both mutant types (B_P225F and B_H272R) have a lower affinity when bound with SDHIs than the WT-BcSDH. The structural and mechanistic insights obtained from the present work will provide a valuable clue for designing novel SDH inhibitors to overcome drug resistance associated with B_P225F and B_H272R mutations.
对琥珀酸脱氢酶抑制剂（SDHIs）具有抗性的灰葡萄孢菌群体是现代农业可持续发展的一个主要问题。在本研究中，揭示了灰葡萄孢菌SDH（BcSDH）中对SDHIs杀菌剂（包括啶酰菌胺（BOS）、戊苯吡菌胺（PEN）、氟吡菌酰胺（PYD）、氟唑菌酰胺（FLU）和苄呋菊酯（BEN））具有抗性的B_P225F和B_H272R突变的抗性机制。生物学测定结果表明，这两种突变对SDHIs表现出不同的抗性因子（RF）。分子模拟结果表明，B_P225F和B_H272R突变对结合口袋的构象变化和抑制剂的结合模式有很大影响。对于这两种突变，配体与C_R88残基之间的阳离子-π相互作用在野生型（WT）中对结合亲和力起重要作用，在B_P225F中降低，在B_H272R中消失。有趣的是，抑制剂与B_R272之间建立了额外的氢键（Hbond），补偿了B_H272R突变导致的结合能降低。结果，两种突变类型（B_P225F和B_H272R）与SDHIs结合时的亲和力均低于WT-BcSDH。从本研究中获得的结构和机制见解将为设计新型SDH抑制剂以克服与B_P225F和B_H272R突变相关的耐药性提供有价值的线索。
