A comparative study of non-native N-acyl l-homoserine lactone analogs in two Pseudomonas aeruginosa quorum sensing receptors that share a common native ligand yet inversely regulate virulence

• Published in: Bioorganic & medicinal chemistry Vol. 26; no. 19; pp. 5336 - 5342
• Main Authors: Boursier, Michelle E., Manson, Daniel E., Combs, Joshua B., Blackwell, Helen E.
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 15.10.2018; Elsevier
• Subjects: 4-Butyrolactone - analogs & derivatives; 4-Butyrolactone - chemical synthesis; 4-Butyrolactone - chemistry; 4-Butyrolactone - pharmacology; Bacterial Proteins - agonists; Bacterial Proteins - antagonists & inhibitors; Bacterial Proteins - metabolism; Biochemistry & Molecular Biology; Chemistry; Chemistry, Medicinal; Chemistry, Organic; LasR; Life Sciences & Biomedicine; Ligands; N-(3-oxo)-dodecanoyl l-homoserine lactone; Pharmacology & Pharmacy; Physical Sciences; Pseudomonas aeruginosa; Pseudomonas aeruginosa - metabolism; Pseudomonas aeruginosa - pathogenicity; QscR; Quorum sensing; Repressor Proteins - agonists; Repressor Proteins - antagonists & inhibitors; Repressor Proteins - metabolism; Science & Technology; Trans-Activators - agonists; Trans-Activators - antagonists & inhibitors; Trans-Activators - metabolism; Virulence - drug effects; LasR; Pseudomonas aeruginosa; Quorum sensing; N-(3-oxo)-dodecanoyl l-homoserine lactone; QscR; DESIGN; CRYSTAL-STRUCTURE; MODULATORS; AUTOINDUCER; SYNTHETIC LIGANDS; INHIBITION; BIOLOGICAL EVALUATION; N-(3-oxo)-dodecanoyl L-homoserine lactone; BIOFILM FORMATION
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2018.05.018

[Display omitted] Certain bacteria can coordinate group behaviors via a chemical communication system known as quorum sensing (QS). Gram-negative bacteria typically use N-acyl l-homoserine lactone (AHL) signals and their cognate intracellular LuxR-type receptors for QS. The opportunistic pathogen Pseudomonas aeruginosa has a relatively complex QS circuit in which two of its LuxR-type receptors, LasR and QscR, are activated by the same natural signal, N-(3-oxo)-dodecanoyl l-homoserine lactone. Intriguingly, once active, LasR activates virulence pathways in P. aeruginosa, while activated QscR can inactivate LasR and thus repress virulence. We have a limited understanding of the structural features of AHLs that engender either agonistic activity in both receptors or receptor-selective activity. Compounds with the latter activity profile could prove especially useful tools to tease out the roles of these two receptors in virulence regulation. A small collection of AHL analogs was assembled and screened in cell-based reporter assays for activity in both LasR and QscR. We identified several structural motifs that bias ligand activation towards each of the two receptors. These findings will inform the development of new synthetic ligands for LasR and QscR with improved potencies and selectivities.