Title: Inhibiting an Epoxide Hydrolase Virulence Factor from Pseudomonas aeruginosa Protects CFTR.
Authors: Bahl, Christopher D; Hvorecny, Kelli L; Bomberger, Jennifer M; Stanton, Bruce A; Hammock, Bruce D; Morisseau, Christophe; Madden, Dean R
Published In Angew Chem Int Ed Engl, (2015 Aug 17)
Abstract: Opportunistic pathogens exploit diverse strategies to sabotage host defenses. Pseudomonas aeruginosa secretes the CFTR inhibitory factor Cif and thus triggers loss of CFTR, an ion channel required for airway mucociliary defense. However, the mechanism of action of Cif has remained unclear. It catalyzes epoxide hydrolysis, but there is no known role for natural epoxides in CFTR regulation. It was demonstrated that the hydrolase activity of Cif is strictly required for its effects on CFTR. A small-molecule inhibitor that protects this key component of the mucociliary defense system was also uncovered. These results provide a basis for targeting the distinctive virulence chemistry of Cif and suggest an unanticipated role of physiological epoxides in intracellular protein trafficking.
PubMed ID: 26136396
MeSH Terms: Cystic Fibrosis Transmembrane Conductance Regulator/metabolism*; Dose-Response Relationship, Drug; Enzyme Inhibitors/chemistry; Enzyme Inhibitors/pharmacology*; Epoxide Hydrolases/antagonists & inhibitors*; Epoxide Hydrolases/metabolism; Models, Molecular; Molecular Structure; Pseudomonas aeruginosa/chemistry*; Pseudomonas aeruginosa/metabolism; Small Molecule Libraries/chemistry; Small Molecule Libraries/pharmacology*; Structure-Activity Relationship; Virulence Factors/antagonists & inhibitors*; Virulence Factors/metabolism