title: Inhibiting an Epoxide Hydrolase Virulence Factor from Pseudomonas aeruginosa Protects CFTR.
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.
authors.affiliation: Department of Biochemistry, Geisel School of Medicine at Dartmouth, 7200 Vail Building, Hanover, NH 03755 (USA) http://www.dartmouth.edu/∼madden.
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Bahl
authors.affiliation: Department of Biochemistry, Geisel School of Medicine at Dartmouth, 7200 Vail Building, Hanover, NH 03755 (USA) http://www.dartmouth.edu/∼madden.
authors.forename: Kelli L
authors.initials: KL
authors.lastname: Hvorecny
authors.affiliation: Department of Microbiology & Immunology, Geisel School of Medicine at Dartmouth, 7560 Vail Building, Hanover, NH 03755 (USA).
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Bomberger
authors.affiliation: Department of Microbiology & Immunology, Geisel School of Medicine at Dartmouth, 7560 Vail Building, Hanover, NH 03755 (USA).
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Stanton
authors.affiliation: Department of Entomology and Nematology, UCD Comprehensive Cancer Center, University of California at Davis, One Shields Ave., Davis, CA 95616 (USA).
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Hammock
authors.affiliation: Department of Entomology and Nematology, UCD Comprehensive Cancer Center, University of California at Davis, One Shields Ave., Davis, CA 95616 (USA).
authors.forename: Christophe
authors.initials: C
authors.lastname: Morisseau
authors.affiliation: Department of Biochemistry, Geisel School of Medicine at Dartmouth, 7200 Vail Building, Hanover, NH 03755 (USA) http://www.dartmouth.edu/∼madden. drm0001@dartmouth.edu.
authors.forename: Dean R
authors.initials: DR
authors.lastname: Madden
mesh_terms: D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D011550:Pseudomonas aeruginosa / Q000737:chemistry* / Q000378:metabolism; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D037521:Virulence Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D054852:Small Molecule Libraries; D037521:Virulence Factors; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D004851:Epoxide Hydrolases
keywords: CFTR; Pseudomonas aeruginosa; epoxide hydrolase; inhibitors; virulence factors