Ocotillol型C-24差向异构体分子探针化学构建及抗MRSA作用机制研究

目前细菌耐药是全世界面临的重要难题，亟需研发化学结构与作用机制新颖的抗菌药物。本课题前期研究证实：二醇型人参皂苷在体内重要代谢产物ocotillol型差向异构体OS/OR及其衍生物，具有良好的抗耐甲氧西林金黄色葡萄球菌（MRSA）活性，与卡那霉素协同抗MRSA活性更为显著，潜在作用靶点位于细菌细胞膜。本项目以探索天然活性产物成药性为目的，靶点探索为核心，构效关系为基础，计算模拟为手段，拟设计合成新型ocotillol母核及衍生物、对膜蛋白具有优势的LDAI型分子探针及ABPP、CC-ABPP型分子探针；通过抗MRSA活性研究，总结C-3侧链、C-24立体构型对药效特异性的影响；以无活性探针为参照，高活性衍生物为竞争，利用高活性探针通过亲和层析、蛋白质凝胶电泳等蛋白组学方法探索该类化合物的抗菌作用靶点。为发现新型抗MRSA候选药物提供依据，为研究具有自主知识产权的抗菌新药奠定基础。

Due to rapidly growing bacterial antibiotic resistance and the shortage of antibacterial agents, bacterial infections are still a global problem. Therefore, it is urgent to develop antibacterial drugs with new chemical structures and new mechanisms. According to our previous study, the ocotillol-type C-24 epimers OS/OR and derivatives, as the important metabolites of protopanaxadiol type saponins in vivo, were shown to have good activity against methicillin-resistant staphylococcus aures (MRSA), and significant synergistic activity against MRSA with kanamycin. The side chain at C-3 and the steric configuration of C-24 were related to the antibacterial activity of these derivatives. The ocotillol-type fluorescent molecular probe was evenly distributed on the bacterial membrane. Based on the goal of the drug discovery, the core of the target exploration, the basis of the structure-activity relationships and the method of computer aided drug design, this project aims to design and synthesize three series of molecular probes, LDAI, ABPP and CC-ABPP molecular probes. LDAI molecular probes have advantages for membrane proteins. The active molecular probes will be used to explore the antibacterial targets through a proteomic approach and by using inactive probes as references, and highly active derivatives as competition. The study will lay a solid foundation for the discovery of new antibacterial candidates and the development of novel antibacterial agents with new structures and modes of action.