Chinese Academy of Sciences, Beijing, China.
Antimicrob Agents Chemother. 2012 Dec;56(12):6088-94. doi: 10.1128/AAC.01119-12. Epub 2012 Jul 16.
In Pseudomonas aeruginosa, the quorum-sensing (QS) system is closely related to biofilm formation. We previously demonstrated that 14-alpha-lipoyl andrographolide (AL-1) has synergistic effects on antibiofilm and antivirulence factors (pyocyanin and exopolysaccharide) of P. aeruginosa when combined with conventional antibiotics, while it has little inhibitory effect on its growth. However, its molecular mechanism remains elusive. Here we investigated the effect of AL-1 on QS systems, especially the Las and Rhl systems. This investigation showed that AL-1 can inhibit LasR-3-oxo-C(12)-homoserine lactone (HSL) interactions and repress the transcriptional level of QS-regulated genes. Reverse transcription (RT)-PCR data showed that AL-1 significantly reduced the expression levels of lasR, lasI, rhlR, and rhlI in a dose-dependent manner. AL-1 not only decreased the expression level of Psl, which is positively regulated by the Las system, but also increased the level of secretion of ExoS, which is negatively regulated by the Rhl system, indicating that AL-1 has multiple effects on both the Las and Rhl systems. It is no wonder that AL-1 showed synergistic effects with other antimicrobial agents in the treatment of P. aeruginosa infections.
在铜绿假单胞菌中，群体感应（QS）系统与生物膜形成密切相关。我们之前证明，当与传统抗生素联合使用时，14-α-二氢乳香酸（AL-1）对铜绿假单胞菌的抗生物膜和抗毒力因子（绿脓菌素和胞外多糖）具有协同作用，而对其生长几乎没有抑制作用。然而，其分子机制仍不清楚。在这里，我们研究了 AL-1 对 QS 系统的影响，特别是 Las 和 Rhl 系统。研究表明，AL-1 可以抑制 LasR-3-氧代-C(12)-高丝氨酸内酯（HSL）相互作用，并抑制 QS 调节基因的转录水平。逆转录（RT）-PCR 数据显示，AL-1 以剂量依赖性方式显著降低了 lasR、lasI、rhlR 和 rhlI 的表达水平。AL-1 不仅降低了 Las 系统正向调节的 Psl 的表达水平，而且增加了 Rhl 系统负向调节的 ExoS 的分泌水平，这表明 AL-1 对 Las 和 Rhl 系统都有多种作用。难怪 AL-1 在治疗铜绿假单胞菌感染时与其他抗菌药物表现出协同作用。
