Synthesis and stability of small molecule probes for Pseudomonas aeruginosa quorum sensing modulation
Synthesis and stability of small molecule probes for Pseudomonas aeruginosa quorum sensing modulation
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DOI：
10.1039/b412802h
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发表时间：
2004-01-01
影响因子：
3.2
通讯作者：
Spring, DR
中科院分区：
文献类型：
--
作者：
Glansdorp, FG;Thomas, GL;Spring, DR
人类病原体铜绿假单胞菌使用N-丁酰-L-高丝氨酸内酯（BHL）和N-（3-氧代十二烷基）-L-高丝氨酸内酯（OdDHL）作为称为群体感应（QS）的现象中的小分子细胞间信号。QS调节剂可有效减弱铜绿假单胞菌的毒力;因此，它们是一类潜在的新型抗菌剂。BHL和OdDHL中的内酯在生理条件下水解。水解以比α-手性中心的外消旋化更快的速率进行。设计并合成了不可水解的非外消旋类似物（小分子探针），用酮代替内酯。发现OdDHL类似物对分解相对不稳定，除非它们在β-酮酰胺之间二氟化。对不可水解的环己酮类似物的稳定性研究表明，α-手性中心的外消旋化相对较慢。对该类似物进行了测定，以表明L-异构体可能是铜绿假单胞菌和沙雷氏菌属菌株ATCC 39006中QS自诱导活性的原因。
The human pathogen Pseudomonas aeruginosa uses N-butyryl-L-homoserine lactone (BHL) and N-(3-oxododecanyl)-L-homoserine lactone (OdDHL) as small molecule intercellular signals in a phenomenon known as quorum sensing (QS). QS modulators are effective at attenuating P. aeruginosa virulence; therefore, they are a potential new class of antibacterial agent. The lactone in BHL and OdDHL is hydrolysed under physiological conditions. The hydrolysis proceeds at a rate faster than racemisation of the alpha-chiral centre. Non-hydrolysable, non-racemic analogues ( small molecule probes) were designed and synthesised, replacing the lactone with a ketone. OdDHL analogues were found to be relatively unstable to decomposition unless they were difluorinated between the beta-keto amide. Stability studies on a non-hydrolysable, cyclohexanone analogue indicated that racemisation of the alpha-chiral centre was relatively slow. This analogue was assayed to show that the L-isomer is likely to be responsible for the QS autoinducing activity in P. aeruginosa and Serratia strain ATCC39006.