耐药性细菌感染已经成为威胁全人类健康的重大疾病之一，基于新型作用靶点与机制开发抗菌新药是解决这一难题的有效途径。FtsZ是细菌分裂的必需蛋白，在细菌分裂繁殖过程中起关键作用，并具有高度的序列保守性，是一个具有开发前景的抗菌药物新靶点。我们的前期研究发现2,4,6-三取代嘧啶衍生物（F06和F07系列）能抑制FtsZ的GTP水解活性和动态聚合，进而抑制细菌生长。本项目以此为基础，将开展以下研究内容：（1）深入研究现有嘧啶衍生物与FtsZ的相互作用机制和结合模式，为优化衍生物提供设计思路；（2）基于FtsZ与底物和抑制剂的结合模式，在2,4,6-三取代嘧啶的结构基础上，设计合成结构多样的FtsZ抑制剂，并进行活性筛选和建立构效关系；（3）挑选代表性衍生物进行抗耐药菌活性评价和作用机制研究。本项目的开展将为靶向FtsZ的抗菌药物研究提供科学依据，也为新型抗菌小分子的开发提供新的思路和方法学参考。

Antibiotic-resistant bacterial infection has become epidemic all over the world. To overcome the drug resistance problem, antibacterial agents targeting at new binding sites become critical to solve this problem. FtsZ, a bacterial cell division protein, has become attractive as a new target for antibacterial agents discovery because it is the most important and conserved protein in bacterial cell division. In previous study, we found that our amine linked 2,4,6-trisubstituted pyrimidine derivatives can inhibit GTPase activity of FtsZ protein, and have strong inhibitory effects on both FtsZ polymerization and the growth of bacteria, including the drug-resistant strains. Based on these findings, we plan to continue this research in the following aspects..(1) Study the mechanism of action on the 2,4,6-trisubstituted pyrimidine derivatives which already synthesized (F06 and F07 derivatives). And interpret their binding modes in the FtsZ protein..(2) Based on the binding modes of GTP/GDP or inhibitors in the FtsZ protein, design and synthesis a small library of novel prymidine derivatives (60-80 compounds), and screening their inhibitory activities against FtsZ and bacterial strains;.(2) Potential hit compounds will be chosen to study their antibacterial activities against drug-resistant strains and the mechanism of action with FtsZ in details, and analyze their structure-activity relationship..This project can provide scientific evidences for the research of FtsZ inhibitors, and will provide new ideas and methodology for the development of novel antibacterial agents.