Modulation of bacterial quorum sensing with synthetic ligands:: Systematic evaluation of N-acylated homoserine lactones in multiple species and new insights into their mechanisms of action
Modulation of bacterial quorum sensing with synthetic ligands:: Systematic evaluation of N-acylated homoserine lactones in multiple species and new insights into their mechanisms of action
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DOI：
10.1021/ja074135h
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发表时间：
2007-11-07
影响因子：
15
通讯作者：
Blackwell, Helen E.
中科院分区：
文献类型：
--
作者：
Geske, Grant D.;O'Neill, Jennifer C.;Blackwell, Helen E.
细菌使用一种低分子量配体的语言来评估它们的种群密度，这一过程被称为群体感应。这种化学信号传导过程在感染性疾病的发病机制和有益的共生中都起着关键作用。人们对合成配体的开发非常感兴趣，这种配体可以拦截群体感应信号并减弱这些不同的结果。群体感应的广谱和物种选择性调节剂作为小分子工具对于复杂的细胞-细胞信号传导过程的基础研究以及未来的生物医学和环境应用具有重要价值。在这里，我们报道了非天然n-酰基化同丝氨酸内酯的设计和合成，并系统评估了这些类似于90种配体的三种革兰氏阴性细菌：致病菌农杆菌和铜绿假单胞菌；模型共生体费氏弧菌。这项研究首次报道并比较了一组配体在多个物种中的活性，并揭示了迄今为止最有效的群体感应合成调节剂。此外，这些配体中的一些在所有三种物种中都表现出激动或拮抗活性，而其他配体仅在一种或两种物种中具有活性。筛选数据的分析表明，这些配体中至少有一部分通过部分激动机制调节群体感应。我们还证明，选择的配体可以抑制或促进弹性蛋白酶B的产生，弹性蛋白酶B是野生型铜绿假单胞菌的关键毒力因子，这取决于它们的浓度。总的来说，这项工作为革兰氏阴性菌群体感应的小分子抑制或激活所需的分子特征提供了广泛的见解。此外，本研究为群体感应途径和反应的进一步研究提供了一套广泛的化学工具。
Bacteria use a language of low molecular weight ligands to assess their population densities in a process called quorum sensing. This chemical signaling process plays a pivotal role both in the pathogenesis of infectious disease and in beneficial symbioses. There is intense interest in the development of synthetic ligands that can intercept quorum-sensing signals and attenuate these divergent outcomes. Both broad-spectrum and species-selective modulators of quorum sensing hold significant value as small-molecule tools for fundamental studies of this complex cell-cell signaling process and for future biomedical and environmental applications. Here, we report the design and synthesis of focused collections of non-native N-acylated homoserine lactones and the systematic evaluation of these similar to 90 ligands across three Gram-negative bacterial species: the pathogens Agrobacterium tumefaciens and Pseudomonas aeruginosa; the model symbiont Vibrio fischeri. This study is the first to report and compare the activities of a set of ligands across multiple species and has revealed some of the most potent synthetic modulators of quorum sensing to date. Moreover, several of these ligands exhibit agonistic or antagonistic activity in all three species, while other ligands are only active in one or two species. Analysis of the screening data revealed that at least a subset of these ligands modulate quorum sensing via a partial agonism mechanism. We also demonstrate that selected ligands can either inhibit or promote the production of elastase B, a key virulence factor in wild-type P. aeruginosa, depending on their concentrations. Overall, this work provides broad insights into the molecular features required for small-molecule inhibition or activation of quorum sensing in Gram-negative bacteria. In addition, this study has supplied an expansive set of chemical tools for the further investigation of quorum-sensing pathways and responses.