Inhibitors of pathogen intercellular signals as selective anti-infective compounds

Lesic, Biliana; Lépine, François; Déziel, Éric; Zhang, Jiangwen; Zhang, Qunhao; Padfield, Katie; Castonguay, Marie-Hélène; Milot, Sylvain; Stachel, Scott; Tzika, A. Aria; Tompkins, Ronald G.; Rahme, Laurence G. (2007). Inhibitors of pathogen intercellular signals as selective anti-infective compounds PLoS Pathogens , vol. 3 , nº 9. p. 1229-1239. DOI: 10.1371/journal.ppat.0030126.

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Résumé

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

Type de document:	Article
Mots-clés libres:	PSEUDOMONAS-QUINOLONE SIGNAL, QUORUM-SENSING INHIBITORS, LUXR-LUXI FAMILY, TRANSCRIPTIONAL REGULATORS, AERUGINOSA VIRULENCE, WHOLE CELLS, INFECTIONS, GENES, IDENTIFICATION, MVFR
Centre:	Centre INRS-Institut Armand Frappier
Date de dépôt:	01 mai 2014 16:09
Dernière modification:	11 janv. 2017 19:13
URI:	http://espace.inrs.ca/id/eprint/2228

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