Abiotic Small
Molecule Inhibitors and Activators of
the LasR Quorum Sensing Receptor in Pseudomonas aeruginosa with Potencies Comparable or Surpassing N‑Acyl
Homoserine Lactones
posted on 2024-03-20, 10:03authored byDaniel
E. Manson, Gene E. Ananiev, Song Guo, Spencer S. Ericksen, Emma E. Santa, Helen E. Blackwell
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.