N-Acyl Homoserine Lactone Analog Modulators of the Pseudomonas aeruginosa RhlI Quorum Sensing Signal Synthase

TitleN-Acyl Homoserine Lactone Analog Modulators of the Pseudomonas aeruginosa RhlI Quorum Sensing Signal Synthase
Publication TypeJournal Article
Year of Publication2019
AuthorsShin, D, Gorgulla, C, Boursier, ME, Rexrode, N, Brown, EC, Arthanari, H, Blackwell, HE, Nagarajan, R
JournalACS Chemical Biology
Volume14
Pagination2305-2314
Date PublishedOct
ISBN Number1554-8929
Abstract

Virulence in the Gram-negative pathogen Pseudomonas aeruginosa relies in part on the efficient functioning of two LuxI/R dependent quorum sensing (QS) cascades, namely, the LasI/R and RhlI/R systems that generate and respond to N-(3-oxo)-dodecanoyl-L-homoserine lactone and N-butyryl-L-homoserine lactone, respectively. The two acyl homoserine lactone (AHL) synthases, LasI and RhlI, use 3-oxododecanoyl-ACP and butyryl-ACP, respectively, as the acyl-substrates to generate the corresponding autoinducer signals for the bacterium. Although AHL synthases represent excellent targets for developing QS modulators in P. aeruginosa, and in other related bacteria, the identification of potent and signal synthase specific inhibitors has represented a significant technical challenge. In the current study, we sought to test the utility of AHL analogs as potential modulators of an AHL synthase and selected RhlI in P. aeruginosa as an initial target. We systematically varied the chemical functionalities of the AHL headgroup, acyl chain tail, and head-to-tail linkage to construct a small library of signal analogs and evaluated them for RhlI modulatory activity. Although the native N-butyryl-L-homoserine lactone did not inhibit RhlI, we discovered that several of our long-chain, unsubstituted acyl-D-homoserine lactones and acyl-D-homocysteine thiolactones inhibited while a few of the 3-oxoacyl-chain counterparts activated the enzyme. Additional mechanistic investigations with acyl-substrate analogs and docking experiments with AHL analogs revealed two distinct inhibitor and activator binding pockets in the enzyme. This study provides the first evidence of the yet untapped potential of AHL analogs as signal synthase modulators of QS pathways.

DOI10.1021/acschembio.9b00671