持留菌休眠分子机制及其基因调控网络的研究

Persister cells refer to a small and rare population of cells, which are produced by their isogenic population of antibiotic-suscesptible bacteria, but exhibit transient tolerance to multiple antibiotic drugs. Persister cells and their formation mechanisms have aroused extensive attention. It is because bacterial persisters is closely related with recurrent infections and chronic infection due to treatment failure, and their long-time existance significantly increases the dangerous potential of gaining exogenous antibiotic resistant genes for the strain. For this study, Acinetobacter baumannii standard strain is going to be used as a persister model, and the persistence-related genomic and transcriptomic data are going to be analyzed based on gaining its complete genome sequences. Using comparative analysis of persistance-related gene regulatory network, the possible underlining molecular mechanisms of persister formation will be throughly explored and discussed. Furthermore, the research objective will gradually expand into clinically important drug resistant bacteria, including Mycobacterium tuberculosis and Escherichia coli, in which, the persistence-related gene network will be constructed from gene expression data, and novel candidate genes and regulatory information will be explored via comparative comparative analysis of the network topology module of different bacterial species. Finally, based on gene network prediction, experimental verification and functional research for persistence-related genes will be conducted for identifying the key regulatory factors in the formation of persisters. This study should provide a theoretical basis for revealing the common mechanism of persisters, and it is of great importance for the future screening of potential drug targets for drug resistant strains.

持留菌是指对抗生素敏感的、同基因型的细菌群体中所出现的一小部分多耐药细菌；其产生不涉及细菌基因组的变异，且耐药表型具有可逆性。持留菌之所以引起广泛关注，是因为细菌持留与反复感染、慢性感染的治疗失败等密切相关。本研究拟在前期获得了鲍曼不动杆菌标准菌株全基因组完成图的基础之上，以其为模式进行持留相关基因的转录组分析并构建基因调控网络，以揭示鲍曼持留菌形成的分子机制。进一步将研究对象扩展到其它重要临床病原菌，包括结核分枝杆菌和大肠杆菌等；利用已知的基因表达数据，搭建模型并预测不同细菌持留相关的基因调控网络。通过对各细菌物种持留网络的拓扑结构模块比较分析，揭示细菌持留相关侯选基因和共性调控模式信息；对重要候选基因进行实验验证和功能研究，进而鉴定出持留菌形成过程中关键的调控因子。本研究的开展将为揭示持留菌产生的共性机制提供理论依据，对今后针对耐药持留菌的潜在药物靶点的筛选具有重要意义。

持留菌是指对抗生素敏感的、同基因型的细菌群体中所出现的一小部分多耐药细菌；其产生不涉及细菌基因组的变异，且耐药表型具有可逆性。持留菌之所以引起广泛关注，是因为细菌持留与反复感染、慢性感染的治疗失败等密切相关。本研究拟在前期获得了鲍曼不动杆菌标准菌株全基因组完成图的基础之上，以其为模式进行持留相关基因的转录组分析并进行层次聚类分析，以揭示鲍曼持留菌形成的分子机制。进一步将研究对象扩展到其它重要临床病原菌，包括结核分枝杆菌和大肠杆菌等；对重要候选基因进行实验验证和功能研究，进而鉴定出持留菌形成过程中关键的调控因子。本研究的开展将为揭示持留菌产生的共性机制提供理论依据，对今后针对耐药持留菌的潜在药物靶点的筛选具有重要意义。