碳青霉烯耐药肺炎克雷伯菌耐药机制与毒力因子及其进化研究

碳青霉烯耐药肺炎克雷伯菌（Carbapenem-resistant Klebsiella pneumoniae，CRKP）感染病死率极高，主要是由于CRKP高耐药性和高致病力及对有效治疗药物也极易产生耐药。近年来，其感染迅速增加，并出现向更高耐药性和更高致病力进化现象，已经出现高耐药性和高毒力整合的CRKP感染，给患者生命带来巨大威胁。申请人长期致力于CRKP耐药、毒力等研究，本项目拟在前期研究基础上采用全基因组二代和三代测序，比较基因组学，基因敲除及回补，单细胞拉曼成像技术，小鼠感染模型等对CRKP耐药及异质性耐药机制、毒力因子、毒力和耐药进化趋势及机制进行系统研究，阐明其对主要抗菌药物的耐药机制，明确其毒力因子分布及关键毒力因子，发现新耐药机制和新毒力因子，揭示CRKP体内和群体进化的趋势和机制。为CRKP感染有效治疗方案及防控新策略制定提供科学依据，并为新抗菌药物研发提供新靶点。

Infections caused by Carbapenem-resistant Klebsiella pneumoniae (CRKP) have extremely high rates of mortality, since CRKP shows the high resistance and virulence and easily becomes resistant to effective antibiotics. CRKP infections have rapidly increased and its evolution towards higher drug resistance and higher virulence has emerged during recent years. Nowadays, CRKP infections with both high drug resistance and high virulence have emerged, posing a tremendous threat to patients. The applicant has long committed to CRKP resistance, virulence and other research. Based on the previous studies, this project intends to use second- and third-generation sequencing technologies, comparative genomics, gene knockout and complementation experiment, single-cell Raman microspectroscopy, murine infection model and other technologies to systematically study the mechanisms of CRKP resistance and heteroresistance, virulence factors, as well as trends and mechanisms of the evolution of resistance and virulence in CRKP. Then to clarify its mechanism of resistance to major antibiotics, to determine the distribution of virulence factors and key virulence factors, to discover new resistance mechanisms and new virulence factors, to reveal the evolution trends and mechanisms of CRKP in vivo and population. This project will provide a scientific basis for the effective treatment of CRKP infections and new strategies of prevention and infection control, also offer new targets for the development of new antibacterial drugs for CRKP.