title: Flavonoids SuppressPseudomonas aeruginosaVirulence through Allosteric Inhibition of Quorum-sensing Receptors.
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 inhibitPseudomonas aeruginosabiofilm 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 toP. aeruginosaalters 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.
authors.affiliation: From the Department of Molecular Biology and.
authors.forename: Jon E
authors.initials: JE
authors.lastname: Paczkowski
authors.affiliation: From the Department of Molecular Biology and.
authors.forename: Sampriti
authors.initials: S
authors.lastname: Mukherjee
authors.affiliation: From the Department of Molecular Biology and.
authors.forename: Amelia R
authors.initials: AR
authors.lastname: McCready
authors.affiliation: From the Department of Molecular Biology and.
authors.forename: Jian-Ping
authors.initials: JP
authors.lastname: Cong
authors.affiliation: CJA MedChem, Hillsborough, North Carolina 27278.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Aquino
authors.affiliation: the Department of Chemistry, Small Molecule Screening Center, Princeton University, Princeton, New Jersey 08544.
authors.forename: Hahn
authors.initials: H
authors.lastname: Kim
authors.affiliation: Opti-Mol Consulting, LLC, Cary, North Carolina 27513, and.
authors.forename: Brad R
authors.initials: BR
authors.lastname: Henke
authors.affiliation: From the Department of Molecular Biology and.
authors.forename: Chari D
authors.initials: CD
authors.lastname: Smith
authors.affiliation: From the Department of Molecular Biology and bbassler@princeton.edu.|the Howard Hughes Medical Institute, Chevy Chase, Maryland 20815.
authors.forename: Bonnie L
authors.initials: BL
authors.lastname: Bassler
mesh_terms: D000494:Allosteric Regulation; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors*; D018441:Biofilms / Q000187:drug effects / Q000254:growth & development; D005419:Flavonoids / Q000494:pharmacology*; D011550:Pseudomonas aeruginosa / Q000187:drug effects* / Q000254:growth & development; D053038:Quorum Sensing / Q000187:drug effects / Q000502:physiology*; D054852:Small Molecule Libraries / Q000494:pharmacology; D013329:Structure-Activity Relationship; D015534:Trans-Activators / Q000037:antagonists & inhibitors*; D014774:Virulence / Q000187:drug effects*
chemical_list: D001426:Bacterial Proteins; D005419:Flavonoids; C080365:LasR protein, Pseudomonas aeruginosa; C086515:RhlR protein, Pseudomonas aeruginosa; D054852:Small Molecule Libraries; D015534:Trans-Activators
keywords: Pseudomonas; flavonoid; inhibition mechanism; quorum sensing; virulence factor