Covalent Inhibition of Bacterial Quorum Sensing
Covalent Inhibition of Bacterial Quorum Sensing
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DOI：
10.1021/ja903292v
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发表时间：
2009-08-05
影响因子：
15
通讯作者：
Meijler, Michael M.
中科院分区：
文献类型：
--
作者：
Amara, Neri;Mashiach, Roi;Meijler, Michael M.
细菌之间基因表达的化学协调作为种群密度的函数，由一种称为“群体感应”（OS）的机制调节。铜绿假单胞菌是一种在免疫功能低下患者中引起疾病的机会致病菌，其QS通过转录激活因子LasR与其配体3-oxo-C-12-HSL的结合介导，导致毒力因子的群体性分泌和生物膜形成。我们使用一组亲电子探针靶向铜绿假单胞菌中的QS，这些探针旨在与LasR结合口袋中的Cys 79共价结合，从而特异性抑制QS调节的基因表达，并同时减少毒力因子分泌和生物膜形成。QS受体共价修饰的第一个例子为研究细菌群体行为的分子机制提供了新的工具，并可能导致靶向细菌毒力的新策略。
Chemical coordination of gene expression among bacteria as a function of population density is regulated by a mechanism known as 'quorum sensing' (OS). QS in Pseudomonas aeruginosa, an opportunistic pathogen that causes disease in immunocompromised patients, is mediated by binding of the transcriptional activator, LasR, to its ligand, 3-oxo-C-12-HSL, leading to population-wide secretion of virulence factors and biofilm formation. We have targeted QS in P. aeruginosa with a set of electrophilic probes designed to covalently bind Cys79 in the LasR binding pocket, leading to specific inhibition of QS-regulated gene expression and concomitant reduction of virulence factor secretion and biofilm formation. This first example of covalent modification of a QS receptor provides a new tool to study molecular mechanisms of bacterial group behavior and could lead to new strategies for targeting bacterial virulence.