细菌群体感受器QseC抑制剂调控巨噬细胞焦亡介导抗菌应答效应的分子机理

抗生素治疗感染最主要的问题是不可避免地诱导细菌耐药，使其临床应用面临严峻挑战。研制不诱导耐药的抗菌药物是未来的新方向和热点。细菌群体感受器抑制剂(QSI)不会给细菌造成选择性生长压力，具有不诱导耐药的独特优点。目前已知所有QSI在体外均无抑菌作用，仅在体内发挥抗菌作用，其机制完全不清楚。我们的前期研究提示，QSI很可能通过抑制细菌毒力因子表达，继而调控机体抗菌免疫应答效应发挥抗菌作用。本课题从阻断细菌QseC群体感受器，抑制毒力因子表达，进而抑制巨噬细胞过度焦亡，启动抗菌免疫应答思路入手，分别评价阻断QseC对巨噬细胞焦亡的发生与抗菌应答效应的影响，探讨阻断QseC后抑制巨噬细胞焦亡与启动巨噬细胞免疫应答效应的分子机理，评价QseC抑制剂对整体感染动物保护效应与抑制巨噬细胞焦亡作用的一致性。旨在阐明QseC抑制剂抗菌作用新机理，提出抑制巨噬细胞过度焦亡抗菌新思路，探索QSI研究新路径。

The wide spread of antibiotic resistant bacteria in the world has become a nightmare to human beings and also is a leading cause of death in severe infection patients. The main problem of antibiotics used in clinical infection treatment is inevitably inducinge bacterial resistance, resulting in effective antibiotics is dwindling. Therefore, the discovery and development of new antibiotic drugs, which do not induce antibiotic resistance among bacteria, is a new trend for new antibiotic agent research. Inhibition of bacterial quorum sensing system (QSS) can inhibit their pathogenicities, but does not cause selective growth pressure on bacteria and does not induce antibitoic resistance. Currently, the development of new type of antibiotic agents targeting QSS has attracted more attention in antibiotic drug research field. However, the antibacterial effect of the currently known QSS inhibitors had no any inhibitory effects on bacteria in vitro. QSS inhibitors only show antibiotic effects in vivo. So far the mechanism of this phenomenon is almost entirely unclear. In this project, based on our gypothesis ---- QseC inhibitor, LED209, ihibits bacterial virulence, and thereafter inhibits pyroptosis of macrophages and activates innate immune response to kill and clear bacteria, In our research, we plan to investigate the research includes to investigate the effectes of LED209 on pyroptosis o and antibacterial immune response of macrophages, to explore the molecular machanisms of macrphage pyroptosis and antimicrobial immune reaponse in macrphages after blockade of bacterial quorum senser QseC, and to evaluate the protective effects of QseC inhibitor on the infected animal model through inhibitoin of macrophage pyroptosis. This study will reveal antibacterial mechanism of QseC inhibitor, propsoe a new concept of antimicrobials via inhibition of macrophage pyroptosis, provide a new idea and strategy on antibiotic drug research, as well as explore new avenues for drug-resistant infection treatment.