Flavonoids Suppress Virulence through Allosteric Inhibition of Quorum-sensing Receptors.

TitleFlavonoids Suppress Virulence through Allosteric Inhibition of Quorum-sensing Receptors.
Publication TypeJournal Article
Year of Publication2017
AuthorsPaczkowski, JE, Mukherjee, S, McCready, AR, Cong, J-P, Aquino, CJ, Kim, H, Henke, BR, Smith, CD, Bassler, BL
JournalJ Biol Chem
Volume292
Issue10
Pagination4064-4076
Date Published2017 03 10
ISSN1083-351X
KeywordsAllosteric Regulation, Bacterial Proteins, Biofilms, Flavonoids, Pseudomonas aeruginosa, Quorum Sensing, Small Molecule Libraries, Structure-Activity Relationship, Trans-Activators, Virulence
Abstract

<p>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.</p>

DOI10.1074/jbc.M116.770552
Alternate JournalJ. Biol. Chem.
PubMed ID28119451
PubMed Central IDPMC5354481
Grant ListR01 GM065859 / GM / NIGMS NIH HHS / United States
R37 GM065859 / GM / NIGMS NIH HHS / United States
T32 GM007388 / GM / NIGMS NIH HHS / United States
/ HHMI / Howard Hughes Medical Institute / United States