肺炎克雷伯菌Tol-Pal系统介导多粘菌素耐药的作用机制

多粘菌素耐药率上升是临床抗多药耐药革兰氏阴性菌感染面临的新挑战，深入阐明其耐药机制、寻找治疗新策略迫在眉睫。肺炎克雷伯菌通过二元调控系统（TCS）CrrAB、PmrAB、PhoPQ以及mgrB突变激活脂多糖修饰使其产生多粘菌素耐药性。迄今为止，多粘菌素的耐药机制尚未完全阐明。Tol-Pal系统对维持细胞膜完整性和稳定性非常重要，课题组前期研究发现CrrB突变可调控Tol-Pal系统的蛋白高表达，该系统功能缺失的突变株对多粘菌素的敏感性增加且细胞外膜通透性增强，有研究报道PmrAB突变株有类似现象，由此推测TCS突变可能通过Tol-Pal系统调控细胞膜重塑，影响多粘菌素耐药性。本项目拟探讨Tol-Pal系统在肺炎克雷伯菌TCS（CrrAB、PmrAB、PhoPQ）突变介导多粘菌素耐药中的作用，结合脂质组学和蛋白组学揭示其具体的作用机制，为寻找控制超级细菌感染新策略奠定基础。

The rising of polymyxin resistance has brought new challenges to the treatment of infections caused by multidrug-resistant Gram-negative bacteria, which makes it urgent for us to understand the resistance mechanism and find new therapeutic strategies. Polymyxin resistance in Klebsiella pneumoniae is mainly mediated by the mutation in the two-component system (TCS) including CrrAB, PmrAB, PhoPQ, and mgrB, which would activate lipopolysaccharide modification. However, the mechanism of polymyxin resistance has not been fully elucidated. The Tol-Pal system has thought to be important for maintaining outer membrane integrity and stability. Our previous study showed that proteins of the Tol-Pal system were significantly up-regulated in the CrrB mutant. When de-active the Tol-Pal system, CrrB mutant showed increased colistin susceptibility and outer membrane permeability. Interestingly, a similar phenomenon was reported in the PmrAB mutant. Thus, we hypothesized that TCS may regulate membrane remodeling through the Tol-Pal system, thereby affecting polymyxin resistance. To test the hypothesis, the role of the Tol-Pal system in TCS (CrrAB, PmrAB, PhoPQ) mediated polymyxin resistance would be investigated. Furthermore, lipidomics and proteomics would be used to elucidate the underlying mechanism of the Tol-Pal system, which may offer valuable information on the management of “superbugs”.