Potent and Selective Synthetic Modulators of a Quorum Sensing Repressor in Pseudomonas aeruginosa Identified from Second-Generation Libraries of N-Acylated L-Homoserine Lactones

Bacteria can coordinate group behavior using chemical signals in a process called quorum sensing (QS). The QS system in the opportunistic pathogen Pseudomonas aeruginosa is largely governed by the LasR receptor and its cognate chemical signal, N-(3-oxo)-dodecanoyl L-homoserine lactone (OdDHL). LasR also appears to share this signal with an orphan LuxR-type receptor in P. aeruginosa, termed QscR, which represses LasR activity. Non-native molecules that modulate QscR would represent valuable tools to study the role of this novel QS repressor protein in P. aeruginosa. We performed a critical analysis of previously identified, non-native N-acylated L-homoserine lactone (AHL) activators and inhibitors of QscR to determine a set of structure-activity relationships (SARs). Based on these SAR data, we designed, synthesized, and screened several second-generation libraries of AHLs for new ligands that could target QscR. These studies revealed the most active AHL agonists and antagonists of QscR reported to date, with activities ranging from nanomolar to low micromolar in a QscR bacterial reporter strain. Several of these AHLs were highly selective for QscR over LasR and other LuxR-type receptors. A small subset of the new QscR activators, however, were also found to inhibit LasR; this demonstrates the exciting potential for the synergistic modulation of these integral P. aeruginosa QS receptors by using a single synthetic compound.