基于组学与微流控芯片技术的肺炎克雷伯菌ESBL耐药表型发生与转换机制的研究

项目名称： 基于组学与微流控芯片技术的肺炎克雷伯菌ESBL耐药表型发生与转换机制的研究

项目编号： No.81470207

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 高占成

作者单位： 北京大学

项目金额： 70万元

中文摘要： 肺炎克雷伯菌（Klebsiella pneumoniae, KP）产超广谱β内酰胺酶（Extended-spectrum β-lactamase, ESBL）是引起临床感染治疗失败的重要原因，但其ESBL耐药表型发生与转换的分子机制仍不明确。我们前期研究发现部分携带ESBL耐药基因的KP菌株仍对抗生素敏感，同时KP耐药表型在不同抗菌药物浓度梯度下存在明显异质性。这种ESBL基因在不同环境下表型沉默与差异表达，可能是其表型在某种关键元件的调控下相互转换的结果。本项目拟对携带ESBL耐药基因而表型阴性KP菌株，在基因组学、转录组学和蛋白组学分析的基础上，结合微流控芯片技术，研究ESBL基因﹙+﹚/表型﹙-﹚KP菌株表型沉默机制，筛选调控ESBL基因表达的关键元件，揭示和解析KP菌株ESBL耐药表型发生和转化的关键环节和分子机制，并对之加以验证，为控制KP耐药性的发生及传播提供新思路。

中文关键词： 肺炎克雷伯菌；超广谱β内酰胺酶；表型转换；多组学；微流控芯片

英文摘要： The extended spectrum β-lactamase (ESBL)-producing Klebsiella pneumoniae (KP) is a major cause for treatment failure of infectious disease. However, the molecular mechanism of its phenotypic occurrence and transformation of ESBL gene in KP have not been completely understood so far. It was found that a certain amount of KP strains harboring ESBL gene were still sensitive to board-spectrum β-lactam antibiotics without resistant phenotype in our pilot study. In addition, some KP strains developed apparent heterogeneity after application of antimicrobial reagents in different concentration. The existence of silence, variation and transformation of ESBL in their phenotypes in different environment is potentially modulated by a certain of pivotal regulating elements. In the current proposing project, we anticipate to deeply investigate the mechanism of the ESBL phenotypic silence in the ESBL genotype﹙+﹚/phenotype﹙-﹚KP strains, to surveil the pivotal regulating elements associated with ESBL gene expression, to decode and verify the molecular mechanism of phenotypic occurrence and transformation of ESBL gene with the application of microfluid chip and multi-omics (such as pangenomics, transcriptomics and proteinomics) analysis. This promising project may put forward an innovative theory for controlling the emerging and dissemination of KP antibiotic resistance.

英文关键词： Klebsiella pneumoniae;extended-spectrum β-lactamase;phenotypic transformation;multi-omics;microfluid chip