群体感应
铜绿假单胞菌
高丝氨酸
非生物成分
微生物学
小分子
生物
病菌
细菌
生物化学
毒力
生态学
遗传学
基因
作者
Daniel E. Manson,Gene E. Ananiev,Song Guo,Spencer S. Ericksen,Emma E. Santa,Helen E. Blackwell
出处
期刊:ACS Infectious Diseases
[American Chemical Society]
日期:2024-03-20
卷期号:10 (4): 1212-1221
标识
DOI:10.1021/acsinfecdis.3c00593
摘要
The opportunistic pathogen Pseudomonas aeruginosa controls almost 10% of its genome, including myriad virulence genes, via a cell-to-cell chemical communication system called quorum sensing (QS). Small molecules that either inhibit or activate QS in P. aeruginosa represent useful research tools to study the role of this signaling pathway in infection and interrogate its viability as an antivirulence target. However, despite active research in this area over the past 20+ years, there are relatively few synthetic compounds known to strongly inhibit or activate QS in P. aeruginosa. Most reported QS modulators in this pathogen are of low potency or have structural liabilities that limit their application in biologically relevant environments such as mimics of the native N-acyl l-homoserine lactone (AHL) signals. Here, we report the results of a high-throughput screen for abiotic small molecules that target LasR, a key QS regulator in P. aeruginosa. We screened a 25,000-compound library and discovered four new structural classes of abiotic LasR modulators. These compounds include antagonists that surpass the potency of all known AHL-type compounds and mimetics thereof, along with an agonist with potency approaching that of LasR's native ligand. The novel structures of this compound set, along with their anticipated robust physicochemical profiles, underscore their potential value as probe molecules to interrogate the roles of QS in this formidable pathogen.
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