Small molecule screen yields inhibitors of pseudomonas homoserine lactone‐induced host responses. (22nd August 2013)

• Record Type: Journal Article
• Authors: Valentine, Cathleen D.; Zhang, Hua; Phuan, Puay‐Wah; Nguyen, Juliane; Verkman, A. S.; Haggie, Peter M.
• Is Part Of: Cellular microbiology. Volume 16:Number 1(2014:Jan.)
• Page Start: 1
• Page End: 14
• Publication Date: 2013-08-22
• Subjects: Microbiology -- Periodicals; Cytology -- Periodicals; Host-parasite relationships -- Periodicals; Microbiology -- Periodicals; Cells -- Periodicals; Microbiologie -- Périodiques; Microbiologie; Relation hôte-parasite; Cytologie; Cellule; Réponse cellulaire; Ressource Internet (Descripteur de forme); Périodique électronique (Descripteur de forme); 579.05
• DOI: 10.1111/cmi.12176
• Languages: English
• ISSNs: 1462-5814

Abstract

<abstract abstract-type="main"> <title>Summary</title> <p> <italic>Pseudomonas aeruginosa</italic> infections are commonly associated with cystic fibrosis, pneumonias, neutropenia and burns. The <italic>P. aeruginosa</italic> quorum sensing molecule <italic>N</italic>‐(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 <italic>P. aeruginosa</italic> virulence. We report here a novel, host‐targeted approach for potential adjunctive anti‐<italic>Pseudomonal</italic> 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‐<italic>a</italic>]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‐<italic>a</italic>]quinolines inhibited C12 action to restore cytokine secretion in LPS‐stimulated cells. Serendipitously, in the absence of an inflammatory stimulus, triazolo[4, 3‐<italic>a</italic>]quinolines prevented C12‐mediated responses, including cytotoxicity, elevation of cytoplasmic calcium, and p38 MAPK phosphorylation. <italic>In vivo</italic> efficacy was demonstrated in a murine model of dermal inflammation involving intradermalC12 administration. The discovery of triazolo[4, 3‐<italic>a</italic>]quinolines provides a pharmacological tool to investigate C12‐mediated host responses, and a potential host‐targeted anti‐<italic>Pseudomonal</italic> therapy.</p> </abstract>