Structure-Based Design and Biological Evaluation of Triphenyl Scaffold-Based Hybrid Compounds as Hydrolytically Stable Modulators of a LuxR-Type Quorum Sensing Receptor

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• 作者：Matthew C. O’Reilly ; Helen E. Blackwell
• 刊名：ACS Infectious Diseases
• 出版年：2016
• 出版时间：January 8, 2016
• 年：2016
• 卷：2
• 期：1
• 页码：32-38
• 全文大小：504K
• ISSN：2373-8227

文摘

Many common bacterial pathogens utilize quorum sensing to coordinate group behaviors and initiate virulence at high cell densities. The use of small molecules to block quorum sensing provides a means of abrogating pathogenic phenotypes, but many known quorum sensing modulators have limitations, including hydrolytic instability and displaying non-monotonic dose curves (indicative of additional targets and/or modes of action). To address these issues, we undertook a structure-based scaffold-hopping approach to develop new chemical modulators of the LasR quorum sensing receptor in Pseudomonas aeruginosa. We combined components from a triphenyl derivative known to strongly agonize LasR with chemical moieties known for LasR antagonism and generated potent LasR antagonists that are hydrolytically stable across a range of pH values. Additionally, many of these antagonists do not exhibit non-monotonic dose effects, delivering probes that inhibit LasR across a wider range of assay conditions relative to known lactone-based ligands.