Inhibitors of Pathogen Intercellular Signals as Selective Anti-Infective Compounds

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Inhibitors of Pathogen Intercellular Signals as Selective Anti-Infective Compounds

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Title: Inhibitors of Pathogen Intercellular Signals as Selective Anti-Infective Compounds
Author: Lesic, Biliana; Lépine, François; Déziel, Eric; Zhang, Qunhao; Padfield, Katie; Castonguay, Marie-Hélène; Milot, Sylvain; Stachel, Scott; Zhang, Jiangwen; Tzika, A. Aria; Tompkins, Ronald Gary; Rahme, Laurence G.

Note: Order does not necessarily reflect citation order of authors.

Citation: Lesic, 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.
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Abstract: Long-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.
Published Version: doi:10.1371/journal.ppat.0030126
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