重新审视 AI-2 群体感应抑制剂：烷基-DPD 类似物和天然产物芬溴内酯的直接比较,Journal of the American Chemical Society

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重新审视 AI-2 群体感应抑制剂：烷基-DPD 类似物和天然产物芬溴内酯的直接比较
Journal of the American Chemical Society ( IF 14.4 ) Pub Date : 2009-11-04 , DOI: 10.1021/ja9066783
Colin A Lowery ₁ , Takumi Abe , Junguk Park , Lisa M Eubanks , Daisuke Sawada , Gunnar F Kaufmann , Kim D Janda

Affiliation

群体感应 (QS) 系统已在多种细菌中被发现，并介导种内和种间的交流。基于 AI-2 的 QS 系统代表了这些提议的种间系统中研究最多的系统，并且已被证明可以调节多种功能，例如生物发光、毒力因子的表达和生物膜形成。因此，调节性化合物（激动剂和拮抗剂）的开发对于研究未知的基于 AI-2 的 QS 系统和细菌感染的潜在治疗具有重要意义。芬溴利特类天然产物对基于 AI-2 的 QS 表现出优异的抑制活性，因此可被视为 AI-2 抑制剂的“黄金标准”。因此，我们试图将芬溴内酯作为我们最近开发的 AI-2 调节剂的烷基-DPD 面板的对照化合物。在此，我们提出了一种普遍研究的芬溴内酯的修订合成，以及芬溴利特和烷基-DPD 类似物之间的直接比较。我们证明，我们的烷基 DPD 类似物是哈维弧菌和鼠伤寒沙门氏菌这两种具有明确 AI-2 QS 系统的生物体中更有效的 QS 抑制剂，因此对广泛接受的芬溴利特衍生化合物作为AI-2抑制的“黄金标准”。

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Revisiting AI-2 Quorum Sensing Inhibitors: Direct Comparison of Alkyl-DPD Analogues and a Natural Product Fimbrolide

Quorum sensing (QS) systems have been discovered in a wide variety of bacteria, and mediate both intra- and interspecies communication. The AI-2-based QS system represents the most studied of these proposed interspecies systems and has been shown to regulate diverse functions such as bioluminescence, expression of virulence factors, and biofilm formation. As such, the development of modulatory compounds, both agonists and antagonists, is of great interest for the study of unknown AI-2-based QS systems and the potential treatment of bacterial infections. The fimbrolide class of natural products has exhibited excellent inhibitory activity against AI-2-based QS and as such may be considered the "gold standard" of AI-2 inhibitors. Thus, we sought to include a fimbrolide as a control compound for our recently developed alkyl-DPD panel of AI-2 modulators. Herein, we present a revised synthesis of a commonly studied fimbrolide as well as a direct comparison between the fimbrolide and alkyl-DPD analogues. We demonstrate that our alkyl-DPD analogues are more potent inhibitors of QS in both Vibrio harveyi and Salmonella typhimurium, the two organisms with defined AI-2 QS systems, and in doing so call into question the widely accepted use of fimbrolide-derived compounds as the "gold standard" of AI-2 inhibition.

更新日期：2009-11-04

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