2-heptyl-3-hydroxy-4-quinolone and Disease-Models--Animal

Pseudomonas aeruginosa (PA) infections can be notoriously difficult to treat and are often accompanied by the development of antimicrobial resistance (AMR). Quorum sensing inhibitors (QSI) acting on PqsR (MvfR) - a crucial transcriptional regulator serving major functions in PA virulence - can enhance antibiotic efficacy and eventually prevent the AMR. An integrated drug discovery campaign including design, medicinal chemistry-driven hit-to-lead optimization and in-depth biological profiling of a new QSI generation is reported. The QSI possess excellent activity in inhibiting pyocyanin production and PqsR reporter-gene with IC

Topics: Animals; Biofilms; Disease Models, Animal; Mice; Pseudomonas aeruginosa; Pseudomonas Infections; Quinolones; Quorum Sensing; Tobramycin

Cis-2-dodecenoic acid (BDSF) is well known for its important functions in intraspecies signaling in Burkholderia cenocepacia. Previous work has also established an important role of BDSF in interspecies and inter-kingdom communications. It was identified that BDSF modulates virulence of Pseudomonas aeruginosa. However, how BDSF interferes with virulence of P. aeruginosa is still not clear.. We report here that BDSF mediates the cross-talk between B. cenocepacia and P. aeruginosa through interference with quorum sensing (QS) systems and type III secretion system (T3SS) of P. aeruginosa. Bioassay results revealed that exogenous addition of BDSF not only reduced the transcriptional expression of the regulator encoding gene of QS systems, i.e., lasR, pqsR, and rhlR, but also simultaneously decreased the production of QS signals including 3-oxo-C12-HSL, Pseudomonas quinolone signal (PQS) and C4-HSL, consequently resulting in the down-regulation of biofilm formation and virulence factor production of P. aeruginosa. Furthermore, BDSF and some of its derivatives are also capable of inhibiting T3SS of P. aeruginosa at a micromolar level. Treatment with BDSF obviously reduced the virulence of P. aeruginosa in both HeLa cell and zebrafish infection models.. These results depict that BDSF modulates virulence of P. aeruginosa through interference with QS systems and T3SS.

Topics: 4-Butyrolactone; Animals; Antibiosis; Bacterial Secretion Systems; Biofilms; Burkholderia cenocepacia; Disease Models, Animal; Epithelial Cells; Fatty Acids, Monounsaturated; Gene Expression Profiling; HeLa Cells; Homoserine; Humans; Pseudomonas aeruginosa; Pseudomonas Infections; Quinolones; Quorum Sensing; Signal Transduction; Virulence; Virulence Factors; Zebrafish