Abstract：
The emergence of phytopathogenic bacteria resistant to antibacterial agents has rendered previously manageable plant diseases intractable, highlighting the need for safe and environmentally responsible agrochemicals. Inhibition of bacterial cell division by targeting bacterial cell division protein FtsZ has been proposed as a promising strategy for developing novel antibacterial agents. We previously identified 4\'-demethylepipodophyllotoxin (DMEP), a naturally occurring substance isolated from the barberry species Dysosma versipellis, as a novel chemical scaffold for the development of inhibitors of FtsZ from the rice blight pathogen Xanthomonas oryzae pv. oryzae (Xoo). Therefore, constructing structure-activity relationship (SAR) studies of DMEP is indispensable for new agrochemical discovery. In this study, we performed a structure-activity relationship (SAR) study of DMEP derivatives as potential XooFtsZ inhibitors through introducing the structure-based virtual screening (SBVS) approach and various biochemical methods. Notably, prepared compound B2, a 4\'-acyloxy DMEP analog, had a 50% inhibitory concentration of 159.4 µM for inhibition of recombinant XooFtsZ GTPase, which was lower than that of the parent DMEP (278.0 µM). Compound B2 potently inhibited Xoo growth in vitro (minimum inhibitory concentration 153 mg L-1) and had 54.9% and 48.4% curative and protective control efficiencies against rice blight in vivo. Moreover, compound B2 also showed low toxicity for non-target organisms, including rice plant and mammalian cell. Given these interesting results, we provide a novel strategy to discover and optimize promising bactericidal compounds for the management of plant bacterial diseases.
摘要：
对抗菌剂具有抗性的植物病原细菌的出现使以前可以控制的植物病害变得棘手，强调对安全和环境负责的农用化学品的需求。通过靶向细菌细胞分裂蛋白FtsZ抑制细菌细胞分裂已被提出作为开发新的抗菌剂的有希望的策略。我们先前鉴定了4'-去乙基恶果鬼臼毒素（DMEP），一种从小檗属植物Dysosmaversipellis中分离出的天然物质，作为一种新型的化学支架，用于从水稻疫病病原体米黄单胞菌pv中开发FtsZ抑制剂。稻米（Xoo）。因此,构建DMEP的结构-活性关系（SAR）研究对于新的农业化学发现是必不可少的。在这项研究中,我们通过引入基于结构的虚拟筛选(SBVS)方法和各种生化方法,对DMEP衍生物作为潜在的XooFtsZ抑制剂进行了构效关系(SAR)研究.值得注意的是,制备的化合物B2，4'-酰氧基DMEP类似物，对重组XooFtsZGTP酶的抑制具有159.4µM的50%抑制浓度，低于亲本DMEP（278.0µM）。化合物B2在体外有效抑制Xoo生长（最小抑制浓度153mgL-1），在体内对水稻疫病的治疗和保护性控制效率分别为54.9％和48.4％。此外，化合物B2对非靶标生物也显示低毒性，包括水稻植物和哺乳动物细胞。鉴于这些有趣的结果，我们提供了一种新的策略来发现和优化有前途的杀菌化合物，以管理植物细菌性疾病。
