基于水稻白叶枯病害调控的砜类新农药创制与分子靶标研究

Plant bacterial diseases, such as rice bacterial leaf blight disease which is caused by Xanthomonasoryzaepv.oryzae(Xoo), are very difficult to prevent and control. In recent years, plant bacteria disease have become a worldwide major concern in agricultural due to their fast epidemic and thereby resulted severe crop damage, reduced yield, and large economic loss. Based on the critical role and huge challenge in preventing and controlling plant bacteria disease, our group have been taken intensive efforts on discovering novel agrochemicals targeting plant bacteria. In this grant proposal, four series of sulfone and thioether compounds are designed, which are derived from different natural active ingredients such as amino oligosaccharides, cinnamic acid, ferulic acid, and other alkyl carboxylic acids, aromatic carboxylic acids, and heterocyclic carboxylic acids. The target compounds will then be bioassayed against rice bacterial leaf blight, and rice bacteria leaf streak, etc. Highly active compounds are expected to be discovered through systematic structure modification of target compounds. Then we will investigate the action mechanism of highly active molecules as well as their interaction modes with target proteins using chemical biology research methods, during which proteomics of rice bacteria leaf blight will be investigated. Light activated coupling technology will be used to capture the target protein in bacteria of highly active molecules. Then the captured protein will then be analyzed and identified using mass spectrometry. And the protein function will also be verified. The immune activation potential of highly active molecules will also be studied through which new anti-bacteria agent for plants are expected to be discovered. Based on the research results of mechanism, target protein identification as well as the acquired pharmacorphore model, systematic structure optimization of highly active compounds will be carried out to find new compounds with higher potential against plant bacteria disease and finally to commercialize then to industrialization as well as field application.

作物细菌性病害，例如由革兰氏阴性菌黄单孢杆菌引起的水稻白叶枯防控是一个世界性重大难题，具有突发性强、流行速度快，病害一旦发生就很难控制、危害损失重的特点。基于防控的重要性与困难的挑战性，以天然源活性物质氨基寡糖素和肉桂酸、阿魏酸等天然有机酸、芳香酸及杂环羧酸为模板，设计合成四类砜类和硫醚衍生物，筛选抗水稻自叶枯和细条病生物活性。通过杂环小分子或砜或硫醚活性小分子衍生修饰合成技术，获得系列高活性候选药物分子。采用化学生物学方法研究候选药物分子与靶标的作用模式，建立适用于水稻白叶枯菌组学方面的研究体系。利用光交联技术对候选药物所结合的菌体及水稻体内蛋白质靶标进行选择性地捕获，再结合蛋白组学技术等手段鉴定捕获的蛋白质靶标，并进行其功能验证。研究调控免疫的分子机制，创制抗水稻白叶枯细菌病害的免疫激活剂。基于药效团模型和分子靶标的基础上合成高效化合物,实现创新药物的产业化。

作物细菌性病害，例如由革兰氏阴性菌黄单孢杆菌引起的水稻白叶枯防控是一个世界性重大难题，具有突发性强、流行速度快，病害一旦发生就很难控制、危害损失重的特点。基于防控的重要性与困难的挑战性，以天然源活性物质肉桂酸、芳香酸及杂环羧酸为模板，设计合成7类新颖结构的砜类和硫醚先导，筛选了抗水稻自叶枯和细条病生物活性。通过杂环小分子或砜或硫醚活性小分子衍生修饰合成技术，获得系列高活性候选药物分子。采用化学生物学方法研究候选药物分子与靶标的作用模式，建立适用于水稻白叶枯菌组学方面的研究体系。利用光交联技术对高活性化合物B7和氟苄噁唑砜候选药物所结合的菌体及水稻体内蛋白质靶标进行选择性地捕获，再结合蛋白组学技术等手段鉴定捕获的蛋白质靶标，并进行其功能验证，研究调控免疫的分子机制，创制抗水稻白叶枯细菌病害的免疫激活剂。发现了3个原创性的先导化合物以及B7原创高活性化合物；创制出氟苄噁唑砜和甲磺酰菌唑二个具有应用前景的抗细菌候选品种；发现了高活性化合物B7和氟苄噁唑砜抗细菌药剂的新作用机制：“氟苄噁唑砜”可以降低水稻白叶枯病菌体内尿卟啉原脱羧酶活性。化合物B7抑制了丙酮酸激酶的活性从而调控水稻白叶枯病菌鞭毛组装。在本学科国际知名期刊J. Agric. Food Chem.、Pest Manag. Sci.等发表21篇标注的SCI论文；授权中国发明专利3项，新申请中国发明专利4项。项目实施以来毕业博士3名、毕业硕士7名，项目承担人受邀报告10次。举办了“绿色植保技术创新国际高端论坛”2次。获国家科技进步奖一项，主办了带领团队入选了全国教育系统先进集体。

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