我国阿奇霉素和三代头孢类抗生素共耐药志贺菌的流行特征与传播进化规律研究

志贺菌引起的细菌性痢疾仍然是一个严重危害公共卫生健康的全球性问题，特别是多重耐药菌株的出现与流行给公共卫生安全带来了更大威胁。本课题组在细菌性痢疾的监测中发现了耐阿奇霉素和三代头孢类抗生素的多重耐药志贺菌的出现与流行，并首次发现了一起水源性菌痢暴发疫情。志贺菌这种罕见耐药表型及其对公共卫生安全的威胁不容忽视。本项目拟在前期工作基础上，深入系统地开展阿奇霉素和三代头孢类抗生素共耐药志贺菌的流行病学监测，明确其在我国的流行特征与变异变迁规律；通过抗生素敏感性试验、耐药基因检测、接合转移、southern杂交、质粒测序等分析，揭示志贺菌对阿奇霉素和三代头孢类抗生素共耐药的分子基础，通过代表性菌株的全基因组测序和生物信息学分析，阐明转座子、质粒等遗传元件在耐药性产生、传播与进化中的作用；通过系统发生分析与种群结构重建，探究共耐药志贺菌在我国的传播演化规律，为我国细菌性痢疾的治疗和防控提供科学依据。

Shigellosis, caused by Shigella genus remains an important public health threat globally. Emerging multidrug-resistant (MDR) isolates have exacerbated the global burden, leading to increased morbidity, mortality, and treatment costs. During the routine surveillance of shigellosis, we identified the emergence and prevalence of MDR isolates with concurrent resistance to azithromycin and third-generation cephalosporins in China, which had even caused a waterborne outbreak of shigellosis. So the potential threat to public health from the changes in prevalence and antimicrobial resistance of Shigella species with resistance to azithromycin and third-generation cephalosporins in Mainland China should not be underestimated. Here we will conduct the study on the epidemiological characteristics and changing trend of the Shigella isolates with resistance to azithromycin and third-generation cephalosporins in Mainland China. Furthermore, we will explore their molecular mechanisms conferring MDR especially resistance to azithromycin and third-generation cephalosporins by using antimicrobial susceptibility testing, resistance genes screening, plasmid conjugation transfer, southern blotting and plasmid sequencing. Then we will select the representative Shigella strains with resistance to azithromycin and third-generation cephalosporins and submit for whole genome sequencing to clarify the role of transposons, insertion/deletion, and plasmids in the development, spread, variation, and evolution of antimicrobial resistance. Additionally, phylogenetic analysis based on single-nucleotide polymorphisms and core-pan genome was performed to elucidate the evolution and dissemination of Shigella isolates with resistance to azithromycin and third-generation cephalosporins in China. In conclusion, our present study can provide the scientific basis for the shigellosis surveillance, early warning and confirmation of the outbreaks, source-tracking, transmission survey, and formulation of the control and prevention strategies.