肠杆菌科细菌是临床重要病原菌。多重耐药、广泛耐药肠杆菌科细菌迅速增加，尤其是碳青霉烯耐药肠杆菌科细菌的流行，使多粘菌素成为治疗该耐药菌感染的最后一道防线。近年来，多粘菌素耐药性迅速增加，使人类面临无药可用的困境。现有研究（包括本课题组前期研究）发现其对多粘菌素耐药主要由染色体介导的双组分调控系统PmrA/B和PhoP/Q和质粒介导的mcr基因调节脂多糖修饰所致。但仍有不少耐药株现有机制不能解释，其耐药基因传播能力和特征仍未阐明。本研究拟在原有研究基础上通过接合试验、高通量全基因组测序、比较基因组学等方法，系统研究多粘菌素耐药机制、耐药传播机制及携带mcr基因对多粘菌素高耐药形成的作用等。系统阐明我国肠杆菌科细菌对多粘菌素耐药的确切机制；明确多粘菌素耐药基因传播机制和传播能力，揭示mcr基因在多粘菌素高耐药菌株形成中的作用；极可能发现新的耐药和传播机制，为我国多粘菌素耐药防控提供科学依据。

Enterobacteriaceae are important clinical pathogens. Multi-drug resistant (MDR) and extensively-drug resistant (XDR) Enterobacteriaceae, especially carbapenem-resistance Enterobacteriaceae (CRE) are dramatically increased, making colistin the last-resort antibiotic for treating infections caused by these resistant pathogens. However, colistin resistance has increased rapidly in recent years, leading to the plight of no drugs available for clinicians. Present studies, including our previous studies, suggest that colistin resistance is caused by the two-component systems of PmrA/B and PhoP/Q mediated by chromosome and plasmid-mediated gene mcr that regulates the modification of lipopolysaccharide (LPS). However, there are still a lot of colistin resistant strains that can not be explained by these existing mechanisms, and the resistance genes’ capacity of transmission and characteristics have not been elucidated. We are going to use filter-mating experiments, high-throughput whole genome sequencing, comparative genomics, genes knockout and complementation tests to clarify the mechanisms of colistin resistance and transfer of Enterobacteriaceae, the function of mcr gene in the formation of high-level resistance to colistin based on our previous studies. We hope to reveal the mechanisms of colistin resistance in Enterobacteriaceae systematacially, clarify the mechanisms and capacity of transfer of mcr gene as well as the function of mcr gene in the formation of high-level resistance to colistin in Enterobacteriaceae. It is expected to find new mechanisms of resistance and transfer and finally find effective prevention and control measures to colistin resistant Enterobacteriaceae.