Flavonoids Suppress Virulence through Allosteric Inhibition of Quorum-sensing Receptors. Author Jon Paczkowski, Sampriti Mukherjee, Amelia McCready, Jian-Ping Cong, Christopher Aquino, Hahn Kim, Brad Henke, Chari Smith, Bonnie Bassler Publication Year 2017 Type Journal Article Abstract Quorum sensing is a process of cell-cell communication that bacteria use to regulate collective behaviors. Quorum sensing depends on the production, detection, and group-wide response to extracellular signal molecules called autoinducers. In many bacterial species, quorum sensing controls virulence factor production. Thus, disrupting quorum sensing is considered a promising strategy to combat bacterial pathogenicity. Several members of a family of naturally produced plant metabolites called flavonoids inhibit biofilm formation by an unknown mechanism. Here, we explore this family of molecules further, and we demonstrate that flavonoids specifically inhibit quorum sensing via antagonism of the autoinducer-binding receptors, LasR and RhlR. Structure-activity relationship analyses demonstrate that the presence of two hydroxyl moieties in the flavone A-ring backbone are essential for potent inhibition of LasR/RhlR. Biochemical analyses reveal that the flavonoids function non-competitively to prevent LasR/RhlR DNA binding. Administration of the flavonoids to alters transcription of quorum sensing-controlled target promoters and suppresses virulence factor production, confirming their potential as anti-infectives that do not function by traditional bacteriocidal or bacteriostatic mechanisms. Keywords Quorum Sensing, Trans-Activators, Biofilms, Pseudomonas aeruginosa, Small Molecule Libraries, Structure-Activity Relationship, Bacterial Proteins, Virulence, Allosteric Regulation, Flavonoids Journal J Biol Chem Volume 292 Issue 10 Pages 4064-4076 Date Published 2017 Mar 10 ISSN Number 1083-351X DOI 10.1074/jbc.M116.770552 Alternate Journal J Biol Chem PMCID PMC5354481 PMID 28119451 PubMedPubMed CentralGoogle ScholarBibTeXEndNote X3 XML