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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• 作者：Grant D. Geske ; Jennifer C. O'Neill ; David M. Miller ; Margrith E. Mattmann ; Helen E. Blackwell
• 刊名：Journal of the American Chemical Society
• 出版年：2007
• 出版时间：November 7, 2007
• 年：2007
• 卷：129
• 期：44
• 页码：13613 - 13625
• 全文大小：447K
• 年卷期：v.129,no.44(November 7, 2007)
• ISSN：1520-5126

文摘

Bacteria use a language of low molecular weight ligands to assess their population densities ina process called quorum sensing. This chemical signaling process plays a pivotal role both in thepathogenesis of infectious disease and in beneficial symbioses. There is intense interest in the developmentof 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 biomedicaland 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 ~90 ligands across threeGram-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 ofligands across multiple species and has revealed some of the most potent synthetic modulators of quorumsensing to date. Moreover, several of these ligands exhibit agonistic or antagonistic activity in all threespecies, while other ligands are only active in one or two species. Analysis of the screening data revealedthat at least a subset of these ligands modulate quorum sensing via a partial agonism mechanism. Wealso demonstrate that selected ligands can either inhibit or promote the production of elastase B, a keyvirulence factor in wild-type P. aeruginosa, depending on their concentrations. Overall, this work providesbroad insights into the molecular features required for small-molecule inhibition or activation of quorumsensing in Gram-negative bacteria. In addition, this study has supplied an expansive set of chemical toolsfor the further investigation of quorum-sensing pathways and responses.