Abiotic Small Molecule Inhibitors and Activators of the LasR Quorum Sensing Receptor in Pseudomonas aeruginosa with Potencies Comparable or Surpassing N -Acyl Homoserine Lactones.
Daniel E MansonGene E AnanievSong GuoSpencer S EricksenEmma E SantaHelen E BlackwellPublished in: ACS infectious diseases (2024)
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.
Keyphrases
- pseudomonas aeruginosa
- small molecule
- high throughput
- single cell
- cystic fibrosis
- biofilm formation
- signaling pathway
- genome wide identification
- candida albicans
- cell therapy
- escherichia coli
- genome wide
- staphylococcus aureus
- acinetobacter baumannii
- protein protein
- transcription factor
- stem cells
- dna methylation
- high resolution
- fatty acid
- mesenchymal stem cells
- oxidative stress
- epithelial mesenchymal transition
- human health
- climate change