Department of Chemistry , University of Wisconsin-Madison , 1101 University Avenue , Madison , Wisconsin 53706 , United States.
ACS Chem Biol. 2019 Feb 15;14(2):186-191. doi: 10.1021/acschembio.8b01079. Epub 2019 Feb 1.
The RhlR quorum sensing (QS) receptor in the pathogen Pseudomonas aeruginosa plays a prominent role in infection, and both antagonism and agonism of RhlR have been shown to negatively regulate important virulence phenotypes. Non-native lactone ligands are known to modulate RhlR activity, but their utility as chemical probes is relatively limited due to hydrolytic instability. Herein, we report our design and biological evaluation of a suite of hybrid AHL analogs with structures merging (1) features of reported lead RhlR ligands and (2) head groups with improved hydrolytic stabilities. The most promising compounds identified were N-acyl l-homocysteine thiolactones, which displayed enhanced stabilities relative to lactones. Moreover, they were highly selective for RhlR over another key QS receptor in P. aeruginosa, LasR. These compounds are among the most potent RhlR modulators known and represent robust chemical tools to dissect the complex roles of RhlR in the P. aeruginosa QS circuitry.
病原菌铜绿假单胞菌中的 RhlR 群体感应（QS）受体在感染中起着重要作用，拮抗和激动 RhlR 均已被证明可负调控重要的毒力表型。已知非天然内酯配体可调节 RhlR 活性，但由于水解不稳定，其作为化学探针的用途相对有限。在此，我们报告了一系列混合 AHL 类似物的设计和生物学评价，这些类似物的结构融合了（1）报道的 RhlR 配体的特征和（2）具有改善水解稳定性的头基。确定的最有前途的化合物是 N-酰基 l-高半胱氨酸硫内酯，与内酯相比，它们的稳定性增强。此外，它们对铜绿假单胞菌中另一个关键 QS 受体 LasR 的选择性高于内酯。这些化合物是已知最有效的 RhlR 调节剂之一，是用于剖析 RhlR 在铜绿假单胞菌 QS 电路中复杂作用的强大化学工具。
