迟缓爱德华氏菌宿主整合因子调节TolC耐药外排泵的研究

细菌抗生素耐药严重危害水产养殖业，其耐药机制中TolC外排泵的作用十分重要被高度关注。本项目基于前期发现迟缓爱德华菌宿主整合因子β亚基（IHFβ）结合巴洛沙星及其复合物调节TolC启动子以及影响丙酮酸代谢通路的基础上，拟系统开展迟缓爱德华菌IHF调节TolC的研究。主要研究IHF对抗生素的应答规律，与抗生素复合物对AcrAB-TolC调控作用以及调节中心碳代谢对AcrAB-TolC调控作用。由于既往无IHF对耐药调节的报道，因而从IHF角度研究TolC的调控具有以下原创性：1）从全局调节因子水平，而不是限于双调节系统水平，揭示对TolC的直接调控机制；2）从全局代谢调节因子层次，阐明代谢对AcrAB-TolC的间接调控作用；3）深入认识抗生素、IHF、TolC和AcrAB的网络调节关系。这些研究将从一个崭新角度来揭示TolC的调节机制，可为控制水产养殖耐药菌提供非抗生素类新药靶点。

Antibiotic-resistant pathogens pose a big challenge to aquacutral industry. Among the antibiotic-resistant mechanisms, TolC efflux pump has been paid attention to since it plays a crucial role in the resistance, and thus regulation of the pump should be furter explored. Based on the previous findings that Edwardsiella tarda integration host factor β (IHFβ) binds antibiotics which regulates the tolC promoter, and affacts pyruvate metabolism, the present propposal investigates E. tarda IHF regulates TolC efflux pump to mainly undestand response patterns of IHF to different classes of antibiotics, regulation of IHF-antibiotic complex to AcrAB-TolC and regulation of central carbon metabolism to AcrAB-TolC. Since information regarding to regulation of IHF to AcrAB-TolC is not available, investigation on regulation of IHF to TolC is original: 1) To disclose direct regulation of TolC at level of global regulator rather than two-component-system; 2) To disclose indirect regulation of AcrAB-TolC by metabolism at level of global regulator; 3) To understand a network regulation among antibiotics, IHF, TolC and AcrAB. These studies will reveall TolC regulation mechanism at a new view to provide a non-antibiotic target for design of new drugs.