Lesic, BilianaLépine, FrançoisDéziel, EricZhang, QunhaoPadfield, KatieCastonguay, Marie-HélèneMilot, SylvainStachel, ScottZhang, JiangwenTzika, A.Tompkins, RonaldRahme, Laurence2011-02-222007Lesic, Biliana, François Lépine, Eric Déziel, Jiangwen Zhang, Qunhao Zhang, Katie Padfield, Marie-Hélène Castonguay, et al. 2007. Inhibitors of pathogen intercellular signals as selective anti-infective compounds. PLoS Pathogens 3(9): e126.1553-7366http://nrs.harvard.edu/urn-3:HUL.InstRepos:4729255Long-term antibiotic use generates pan-resistant super pathogens. Anti-infective compounds that selectively disrupt virulence pathways without affecting cell viability may be used to efficiently combat infections caused by these pathogens. A candidate target pathway is quorum sensing (QS), which many bacterial pathogens use to coordinately regulate virulence determinants. The Pseudomonas aeruginosa MvfR-dependent QS regulatory pathway controls the expression of key virulence genes; and is activated via the extracellular signals 4-hydroxy-2-heptylquinoline (HHQ) and 3,4-dihydroxy-2-heptylquinoline (PQS), whose syntheses depend on anthranilic acid (AA), the primary precursor of 4-hydroxy-2-alkylquinolines (HAQs). Here, we identified halogenated AA analogs that specifically inhibited HAQ biosynthesis and disrupted MvfR-dependent gene expression. These compounds restricted P. aeruginosa systemic dissemination and mortality in mice, without perturbing bacterial viability, and inhibited osmoprotection, a widespread bacterial function. These compounds provide a starting point for the design and development of selective anti-infectives that restrict human P. aeruginosa pathogenesis, and possibly other clinically significant pathogens.en-USchemical biologyinfectious diseasesmicrobiologyin vitroanimalsmus (mouse)Journal Article2011-02-2210.1371/journal.ppat.0030126