病原菌的群体感应及其抑制剂的研究进展

随着病原菌耐药性特别是多重耐药性的日益严重,抗菌药作用新靶点的发现和新型抗菌药物的研发显得尤为重要.病原菌的致病作用常受到与其群体密度相关的群体感应(quorum-sensing,QS)系统的调控.细菌通过释放和交换自诱导信号分子(autoinducers,AIs)以调控致病相关基因的表达,从而影响细菌的毒力、黏附和生物膜的形成等.不同种类的AIs介导不同的QS系统,阻止AIs的积累或其与受体的识别和结合就可以抑制QS调控的致病基因的表达.因此,QS抑制剂(quorum-sensing inhibitors,QSIs)有望成为控制病原菌感染和耐药性产生的有效武器.迄今发现的QSIs有非肽类小分子化合物、肽类化合物和蛋白质(包括淬灭QS的酶和抗体).此外,一些竞争性的细菌或动物也可以清除AIs从而起到QSIs的作用.QSIs可以通过天然的QSIs指示菌株、人工构建的工程菌或者计算机模拟等方法进行筛选.对QS介导的病原菌致病机理的不断深入研究将为新型的QSI靶标的选择提供帮助,通过将QSIs和传统抗菌药物联合使用有望达到更好的治疗效果并预防细菌耐药性的产生.

Quorum sensing of pathogenic bacteria and quorum-sensing inhibitors

The emergence of antibiotic-resistant and especially multidrug-resistant pathogenic bacteria intensifies the need to screen new drug targets and develop new antibacterial drugs. Bacteria coordinate their virulent behaviors in a cell density-dependent manner known as quorum sensing (QS). In this process, pathogenic bacteria exchange autoinducers (AIs) to regulate the expression of genes involved in processes such as virulence, adhesion, and biofilm formation. Different types of AIs mediate different QS systems. Preventing the accumulation of AIs or blocking their recognition by signal receptors can reduce the pathogenic processes under QS control. Therefore, quorum-sensing inhibitors (QSIs) may be an effective way to treat bacterial infections, especially those caused by antibiotic-resistant strains. QSIs can be categorized into three classes: nonpeptide small molecules, peptides, and proteins (including quorum-quenching enzymes and antibodies). In addition, competing bacteria and animal hosts can scavenge AIs, thus playing the role of QSIs. QSIs can be screened by natural QSI indicator strains, engineered bacteria, or computer simulation. The continuing study of QS-mediated pathogenic mechanisms will provide new targets for QSIs. The combined use of QSIs and traditional antimicrobials is expected to improve treatment and help prevent the further development of drug resistance.