群体感应(QS)是一种细胞-细胞信号系统,使细菌能够协调依赖于种群密度的行为变化。该化学通讯途径由革兰氏阴性细菌中的可扩散N-酰基L-高丝氨酸内酯信号和细胞质信号响应性LuxR型受体介导。由于许多常见的致病菌使用QS来调节毒力,破坏QS作为一种潜在的治疗策略有很大的兴趣.先前的研究涉及天然产物水杨酸,肉桂醛,和其他相关的苯甲醛衍生物作为条件致病菌铜绿假单胞菌中QS的抑制剂,然而,我们对这些化合物的作用机制缺乏了解。在这里,我们使用铜绿假单胞菌LasR和RhlRQS信号受体的异源报告基因评估了一组苯甲醛衍生物的活性。我们发现,大多数测试的苯甲醛衍生物可以在微摩尔浓度下拮抗LasR或RhlR报道基因活化,尽管某些分子也会引起轻度生长缺陷和非特异性报道分子拮抗作用。值得注意的是,几种化合物在低于引起毒性的浓度范围内显示出有希望的RhlR或LasR特异性抑制活性。原香兰素,一种以前未经测试的化合物,是这一组中最有希望的。针对LasR和RhlR的天然配体的竞争实验表明,邻香兰素可以与RhlR竞争,但不能与LasR竞争。总的来说,这些研究扩展了我们对LasR和RhlR受体中苯甲醛活性的理解,并揭示了邻香草醛作为小分子QS调节剂对RhlR的潜在有希望的作用。
目的:群体感应(QS)调节细菌发病机制的许多方面,并在过去的30年中作为抗毒力治疗的靶标引起了极大的兴趣,例如,铜绿假单胞菌中的LasR和RhlRQS受体拮抗剂。强效和选择性QS抑制剂仍然相对稀缺。然而,天然产物提供了大量具有抗QS活性的化学支架,但它们的分子机制缺乏表征。当前的研究通过检查一类重要且广泛的天然产物QS调节剂的活性来填补这一空白,苯甲醛,和相关的衍生品,在LasR和RhlR.我们证明邻香兰素可以作为RhlR的竞争性抑制剂,一种已经出现并可能在某些情况下取代LasR作为铜绿假单胞菌QS控制靶标的受体。本文提供的结果和见解将推进化学工具的设计以研究具有改进的活性和选择性的QS。
Quorum sensing (QS) is a cell-cell signaling system that enables bacteria to coordinate population density-dependent changes in behavior. This chemical communication pathway is mediated by diffusible N-acyl L-homoserine lactone signals and cytoplasmic signal-responsive LuxR-type receptors in Gram-negative bacteria. As many common pathogenic bacteria use QS to regulate virulence, there is significant interest in disrupting QS as a potential therapeutic strategy. Prior studies have implicated the natural products salicylic acid, cinnamaldehyde, and other related benzaldehyde derivatives as inhibitors of QS in the opportunistic pathogen Pseudomonas aeruginosa, yet we lack an understanding of the mechanisms by which these compounds function. Herein, we evaluate the activity of a set of benzaldehyde derivatives using heterologous reporters of the P. aeruginosa
LasR and RhlR QS signal receptors. We find that most tested benzaldehyde derivatives can antagonize
LasR or RhlR reporter activation at micromolar concentrations, although certain molecules also cause mild growth defects and nonspecific reporter antagonism. Notably, several compounds showed promising RhlR or
LasR-specific inhibitory activities over a range of concentrations below that causing toxicity. ortho-Vanillin, a previously untested compound, was the most promising within this set. Competition experiments against the native ligands for
LasR and RhlR revealed that ortho-vanillin can interact competitively with RhlR but not with
LasR. Overall, these studies expand our understanding of benzaldehyde activities in the LasR and RhlR receptors and reveal potentially promising effects of ortho-vanillin as a small molecule QS modulator against RhlR.
OBJECTIVE: Quorum sensing (QS) regulates many aspects of bacterial pathogenesis and has attracted much interest as a target for anti-virulence therapies over the past 30 years, for example, antagonists of the LasR and RhlR QS receptors in Pseudomonas aeruginosa. Potent and selective QS inhibitors remain relatively scarce. However, natural products have provided a bounty of chemical scaffolds with anti-QS activities, but their molecular mechanisms are poorly characterized. The current study serves to fill this void by examining the activity of an important and wide-spread class of natural product QS modulators, benzaldehydes, and related derivatives, in LasR and RhlR. We demonstrate that ortho-vanillin can act as a competitive inhibitor of RhlR, a receptor that has emerged and may supplant LasR in certain settings as a target for P. aeruginosa QS control. The results and insights provided herein will advance the design of chemical tools to study QS with improved activities and selectivities.