FtsZ是MRSA、VRE等耐药性致病菌细胞分裂所必需的蛋白，且高度保守。结构与功能研究揭示FtsZ是一个具有应用前景的抗菌（特别是抗耐药菌）药物新靶点，已有个别FtsZ抑制剂在进行临床前研究。申请人前期研究，发现了中药常山有效成分常山碱Febrifugine衍生物(CS08-13)能有效抑制FtsZ活性和干扰其聚合自组装过程，具有良好抗耐药菌活性。本项目将在此基础上，（1）深入系统研究衍生物CS08-13与FtsZ的相互作用机制和结合模式，为进一步优化新型FtsZ抑制剂提供设计思路；（2）基于FtsZ结构生物学及其与CS08-13相互作用的信息，以Febrifugine为基本骨架，通过分子模拟对接，设计合成结构多样的FtsZ抑制剂小分子库；（3）研究这类化合物抑制作用的构效关系，不断优化分子结构，寻找新型先导化合物；（4）进行先导化合物的抗菌作用机理研究和初步成药性评价。

FtsZ is an essential and highly conserved bacterial cell division protein, even in drug resistant bacteria MRSA and VRE. Study on the structure and function of FtsZ has revealed that FtsZ is a new target for anti-MRSA agent discovery. Because of current FtsZ inhibitors with low selective inhibition and poor clinical efficacy, no FtsZ inhibitor is approved by FAD untill now. In the previous research, we found that a derivative (CS08-13) of Febrifugine, a quinazolinoe alkaloid isolated from Chinese herb Dichroa febrifuga, was identified as potent FtsZ inhibitor with strongly inhibition on the proliferation of MRSA and VER. Based on previous result, this proposal plans to (1) continuously study the interaction mechanism between Febrifugine derivative CS08-13 and FtsZ and their binding mode;(2) and the structure-activity relationship; (2) design and synthesize noval small moleculars library based on skeleton of Febrifugine with computer aid; (3) study their inhibitory activities and structure-activity relationship, keep on optimizing the structure of molecules till finding new lead compound; (4) study the anti-MRSA activity and related mechanisms and druggability of lead compound.