通过群体感应模拟物抑制野生型细胞中铜绿假单胞菌毒力因子绿脓菌素的产生。

Inhibition of the production of the Pseudomonas aeruginosa virulence factor pyocyanin in wild-type cells by quorum sensing autoinducer-mimics.

机构信息

Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, UK.

出版信息

Org Biomol Chem. 2012 Nov 14;10(42):8452-64. doi: 10.1039/c2ob26501j. Epub 2012 Sep 27.

Abstract

Pseudomonas aeruginosa is a notorious human pathogen associated with a range of life-threatening nosocomial infections. There is an increasing problem of antibiotic resistance in P. aeruginosa, highlighted by the emergence of multi-drug resistant strains. Thus the exploration of new strategies for the treatment of P. aeruginosa infections is clearly warranted. P. aeruginosa is known to produce a range of virulence factors that enhance its ability to damage the host tissue and cause disease. One of the most important virulence factors is pyocyanin. P. aeruginosa regulates pyocyanin production using an intercellular communication mechanism called quorum sensing, which is mediated by small signalling molecules termed autoinducers. One native autoinducer is N-(3-oxododecanoyl)-L-homoserine lactone (OdDHL). Herein we report the synthesis of a collection of abiotic OdDHL-mimics. A number of novel compounds capable of competing with the endogenous OdDHL and consequently, inhibiting the production of pyocyanin in cultures of wild type P. aeruginosa were identified. We present evidence suggesting that compounds of this general structural type act as direct antagonists of quorum sensing in P. aeruginosa and as such may find value as molecular tools for the study and manipulation of this signalling pathway. A direct quantitative comparison of the pyocyanin suppressive activities of the most active OdDHL-mimics with some previously-reported inhibitors (based around different general structural frameworks) of quorum sensing from the literature, was also made.

摘要

铜绿假单胞菌是一种臭名昭著的人类病原体,与一系列危及生命的医院获得性感染有关。铜绿假单胞菌对抗生素的耐药性问题日益严重,多药耐药株的出现就是明证。因此,探索治疗铜绿假单胞菌感染的新策略显然是必要的。铜绿假单胞菌会产生一系列毒力因子,增强其破坏宿主组织和引起疾病的能力。其中最重要的毒力因子之一是绿脓菌素。铜绿假单胞菌通过一种称为群体感应的细胞间通讯机制来调节绿脓菌素的产生,这种机制由称为自诱导物的小信号分子介导。一种天然的自诱导物是 N-(3-氧代十二酰基)-L-高丝氨酸内酯(OdDHL)。在此,我们报告了一系列非生物 OdDHL 类似物的合成。鉴定出了许多能够与内源性 OdDHL 竞争并因此抑制野生型铜绿假单胞菌培养物中绿脓菌素产生的新型化合物。我们提供的证据表明,这种一般结构类型的化合物在铜绿假单胞菌中充当群体感应的直接拮抗剂,因此可能作为研究和操纵该信号通路的分子工具具有价值。还对最有效的 OdDHL 类似物的绿脓菌素抑制活性与文献中报道的一些先前的群体感应抑制剂(基于不同的一般结构框架)进行了直接的定量比较。

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