Mechanism of agonism and antagonism of the Pseudomonas aeruginosa quorum sensing regulator QscR with non‐native ligands

• Published in: Molecular microbiology Vol. 108; no. 3; pp. 240 - 257
• Main Authors: Wysoczynski‐Horita, Christina L., Boursier, Michelle E., Hill, Ryan, Hansen, Kirk, Blackwell, Helen E., Churchill, Mair E. A.
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01.05.2018
• Subjects: Bacterial Proteins - agonists; Bacterial Proteins - antagonists & inhibitors; Bacterial Proteins - metabolism; Binding; Deoxyribonucleic acid; Detection; Dimerization; DNA; Gene expression; Ligands; Opportunist infection; Protein Binding; Pseudomonas aeruginosa; Pseudomonas aeruginosa - genetics; Quorum Sensing - physiology; Repressor Proteins - agonists; Repressor Proteins - antagonists & inhibitors; Repressor Proteins - metabolism; RhlR protein; Signal reception; Signal Transduction; Trans-Activators - metabolism; Transcription factors; Transcription Factors - metabolism; Virulence; Virulence - genetics
• ISSN: 0950-382X; 1365-2958
• DOI: 10.1111/mmi.13930

Summary Pseudomonas aeruginosa is an opportunistic pathogen that uses the process of quorum sensing (QS) to coordinate the expression of many virulence genes. During quorum sensing, N‐acyl‐homoserine lactone (AHL) signaling molecules regulate the activity of three LuxR‐type transcription factors, LasR, RhlR and QscR. To better understand P. aeruginosa QS signal reception, we examined the mechanism underlying the response of QscR to synthetic agonists and antagonists using biophysical and structural approaches. The structure of QscR bound to a synthetic agonist reveals a novel mode of ligand binding supporting a general mechanism for agonist activity. In turn, antagonists of QscR with partial agonist activity were found to destabilize and greatly impair QscR dimerization and DNA binding. These results highlight the diversity of LuxR‐type receptor responses to small molecule agonists and antagonists and demonstrate the potential for chemical strategies for the selective targeting of individual QS systems. LuxR‐type transcription factors mediate acyl‐homoserine lactone signaling during Pseudomonas aeruginosa quorum sensing. Biophysical and structural studies of the quorum sensing control receptor (QscR) with synthetic ligands reveal distinct characteristics of agonist and antagonist actions. Increased dimerization and stability of QscR induced by agonists is favorable for DNA recognition, but QscR with antagonists is more labile and less competent to recognize DNA. These findings reveal new strategies for antagonizing quorum sensing.