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. mvfR mutants of PA14 and control PA14 cells were grown to OD 2.5, a point where QS is turned on, and their expression profiles were compared. AA analogs 4CABA and 6CABA were added directly to the culture media of PA14 cells.