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。

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.