Pseudomonas aeruginosa PA14, mvfR and anthranilic acid analogs

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). 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.

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Lesic B, Lépine F, Déziel E, Zhang J, Zhang Q, Padfield K, Castonguay MH, Milot S, Stachel S, Tzika AA, Tompkins RG, Rahme LG