title: A quorum-sensing inhibitor blocks Pseudomonas aeruginosa virulence and biofilm formation.
abstract: Quorum sensing is a chemical communication process that bacteria use to regulate collective behaviors. Disabling quorum-sensing circuits with small molecules has been proposed as a potential strategy to prevent bacterial pathogenicity. The human pathogen Pseudomonas aeruginosa uses quorum sensing to control virulence and biofilm formation. Here, we analyze synthetic molecules for inhibition of the two P. aeruginosa quorum-sensing receptors, LasR and RhlR. Our most effective compound, meta-bromo-thiolactone (mBTL), inhibits both the production of the virulence factor pyocyanin and biofilm formation. mBTL also protects Caenorhabditis elegans and human lung epithelial cells from killing by P. aeruginosa. Both LasR and RhlR are partially inhibited by mBTL in vivo and in vitro; however, RhlR, not LasR, is the relevant in vivo target. More potent antagonists do not exhibit superior function in impeding virulence. Because LasR and RhlR reciprocally control crucial virulence factors, appropriately tuning rather than completely inhibiting their activities appears to hold the key to blocking pathogenesis in vivo.
authors.affiliation: Departments of Molecular Biology, Chemistry, and Mechanical and Aerospace Engineering, Princeton University, Princeton, NJ 08544.
authors.forename: Colleen T
authors.initials: CT
authors.lastname: O'Loughlin
authors.forename: Laura C
authors.initials: LC
authors.lastname: Miller
authors.forename: Albert
authors.initials: A
authors.lastname: Siryaporn
authors.forename: Knut
authors.initials: K
authors.lastname: Drescher
authors.forename: Martin F
authors.initials: MF
authors.lastname: Semmelhack
authors.forename: Bonnie L
authors.initials: BL
authors.lastname: Bassler
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors*; D018441:Biofilms / Q000254:growth & development*; D017173:Caenorhabditis elegans; D002460:Cell Line; D004926:Escherichia coli; D006801:Humans; D007783:Lactones / Q000737:chemistry / Q000494:pharmacology; D046228:Microarray Analysis; D015394:Molecular Structure; D011550:Pseudomonas aeruginosa / Q000472:pathogenicity* / Q000502:physiology; D011710:Pyocyanine; D053038:Quorum Sensing / Q000187:drug effects / Q000502:physiology*; D020545:Respiratory Mucosa / Q000502:physiology; D013457:Sulfur Compounds / Q000737:chemistry / Q000494:pharmacology; D015534:Trans-Activators / Q000037:antagonists & inhibitors*; D014774:Virulence
chemical_list: D001426:Bacterial Proteins; D007783:Lactones; C080365:LasR protein, Pseudomonas aeruginosa; C086515:RhlR protein, Pseudomonas aeruginosa; D013457:Sulfur Compounds; D015534:Trans-Activators; D011710:Pyocyanine