1,3,4-Oxadiazole thioethers have shown exciting antibacterial activities; however, the current mechanism of action involving such substances against bacteria is limited to proteomics-mediated protein pathways and differentially expressed gene analysis. Herein, we report a series of novel 1,3,4-oxadiazole thioethers containing a carboxamide/amine moiety, most of which show good in vitro and in vivo bacteriostatic activities. Compounds A₁₀ and A₁₈ were screened through CoMFA models as optimums against Xanthomonas oryzae pv. oryzae (Xoo, EC₅₀ values of 5.32 and 4.63 mg/L, respectively) and Xanthomonas oryzae pv. oryzicola (Xoc, EC₅₀ values of 7.58 and 7.65 mg/L, respectively). Compound A₁₀ was implemented in proteomic techniques and activity-based protein profiling (ABPP) analysis to elucidate the antibacterial mechanism and biochemical targets. The results indicate that A₁₀ disrupts the growth and pathogenicity of Xoc by interfering with pathways associated with bacterial virulence, including the two-component regulation system, flagellar assembly, bacterial secretion system, quorum sensing, ABC transporters, and bacterial chemotaxis. Specifically, the translational regulator (CsrA) and the virulence regulator (Xoc3530) are two effective target proteins of A₁₀. Knocking out the CsrA or Xoc3530 gene in Xoc results in a significant reduction in the motility and pathogenicity of the mutant strains. This study contributes available molecular entities, effective targets, and mechanism basis for the management of rice bacterial diseases.

中文翻译：

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5-(硫醚)-N-苯基/苄基-1,3,4-恶二唑-2-甲酰胺/胺衍生物的合成、生物活性及抗菌机制

1,3,4-恶二唑硫醚显示出令人兴奋的抗菌活性；然而，目前涉及此类物质对抗细菌的作用机制仅限于蛋白质组学介导的蛋白质途径和差异表达基因分析。在此，我们报道了一系列含有甲酰胺/胺部分的新型1,3,4-恶二唑硫醚，其中大多数表现出良好的体外和体内抑菌活性。通过 CoMFA 模型筛选了化合物A ₁₀和A ₁₈作为针对米黄单胞菌pv 的最佳化合物。米霉（Xoo， EC ₅₀值分别为 5.32 和 4.63 mg/L）和米黄单胞菌pv。oryzicola（Xoc、EC ₅₀值分别为 7.58 和 7.65 mg/L）。化合物A ₁₀采用蛋白质组学技术和基于活性的蛋白质分析 (ABPP) 分析来阐明抗菌机制和生化靶点。结果表明，A ₁₀通过干扰与细菌毒力相关的途径（包括双组分调节系统、鞭毛组装、细菌分泌系统、群体感应、ABC 转运蛋白和细菌趋化性）来破坏Xoc的生长和致病性。具体而言，翻译调节因子（CsrA）和毒力调节因子（Xoc3530）是A ₁₀的两个有效靶蛋白。敲除Xoc中的CsrA或Xoc3530基因会导致突变株的运动性和致病性显着降低。该研究为水稻细菌性病害的防治提供了可用的分子实体、有效靶点和机制基础。