title: Small molecule screen yields inhibitors of Pseudomonas homoserine lactone-induced host responses.
abstract: Pseudomonas aeruginosa infections are commonly associated with cystic fibrosis, pneumonias, neutropenia and burns. The P. aeruginosa quorum sensing molecule N-(3-oxo-dodecanoyl) homoserine lactone (C12) cause multiple deleterious host responses, including repression of NF-κB transcriptional activity and apoptosis. Inhibition of C12-mediated host responses is predicted to reduce P. aeruginosa virulence. We report here a novel, host-targeted approach for potential adjunctive anti-Pseudomonal therapy based on inhibition of C12-mediated host responses. A high-throughput screen was developed to identify C12 inhibitors that restore NF-κB activity in C12-treated, lipopolysaccharide (LPS)-stimulated cells. Triazolo[4,3-a]quinolines with nanomolar potency were identified as C12-inhibitors that restore NF-κB-dependent luciferase expression in LPS- and TNF-stimulated cell lines. In primary macrophages and fibroblasts, triazolo[4,3-a]quinolines inhibited C12 action to restore cytokine secretion in LPS-stimulated cells. Serendipitously, in the absence of an inflammatory stimulus, triazolo[4,3-a]quinolines prevented C12-mediated responses, including cytotoxicity, elevation of cytoplasmic calcium, and p38 MAPK phosphorylation. In vivo efficacy was demonstrated in a murine model of dermal inflammation involving intradermalC12 administration. The discovery of triazolo[4,3-a]quinolines provides a pharmacological tool to investigate C12-mediated host responses, and a potential host-targeted anti-Pseudomonal therapy.
authors.affiliation: Division of Nephrology, Department of Medicine, University of California San Francisco, San Francisco, CA, 94143, USA.
authors.forename: Cathleen D
authors.initials: CD
authors.lastname: Valentine
authors.forename: Hua
authors.initials: H
authors.lastname: Zhang
authors.forename: Puay-Wah
authors.initials: PW
authors.lastname: Phuan
authors.forename: Juliane
authors.initials: J
authors.lastname: Nguyen
authors.forename: A S
authors.initials: AS
authors.lastname: Verkman
authors.forename: Peter M
authors.initials: PM
authors.lastname: Haggie
mesh_terms: D015107:4-Butyrolactone / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000633:toxicity; D000818:Animals; D000900:Anti-Bacterial Agents / Q000302:isolation & purification* / Q000494:pharmacology; D002478:Cells, Cultured; D004353:Drug Evaluation, Preclinical; D057166:High-Throughput Screening Assays; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D011550:Pseudomonas aeruginosa / Q000276:immunology / Q000502:physiology*; D011804:Quinolines / Q000302:isolation & purification* / Q000494:pharmacology; D015398:Signal Transduction; D037521:Virulence Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000633:toxicity
chemical_list: D000900:Anti-Bacterial Agents; D016328:NF-kappa B; D011804:Quinolines; D037521:Virulence Factors; C088386:homoserine lactone; D015107:4-Butyrolactone
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