title: Discovery and Characterization of a Class of Pyrazole Inhibitors of Bacterial Undecaprenyl Pyrophosphate Synthase.
abstract: Undecaprenyl pyrophosphate synthase (UppS) is an essential enzyme in bacterial cell wall synthesis. Here we report the discovery of Staphylococcus aureus UppS inhibitors from an Encoded Library Technology screen and demonstrate binding to the hydrophobic substrate site through cocrystallography studies. The use of bacterial strains with regulated uppS expression and inhibitor resistant mutant studies confirmed that the whole cell activity was the result of UppS inhibition, validating UppS as a druggable antibacterial target.
authors.affiliation: GlaxoSmithKline , 1250 S. Collegeville Road, Collegeville, Pennsylvania 19426, United States.
authors.forename: Nestor
authors.initials: N
authors.lastname: Concha
authors.affiliation: GlaxoSmithKline , 1250 S. Collegeville Road, Collegeville, Pennsylvania 19426, United States.
authors.forename: Jianzhong
authors.initials: J
authors.lastname: Huang
authors.affiliation: GlaxoSmithKline , 830 Winter Street, Waltham, Massachusetts 02451, United States.
authors.forename: Xiaopeng
authors.initials: X
authors.lastname: Bai
authors.affiliation: GlaxoSmithKline , 1250 S. Collegeville Road, Collegeville, Pennsylvania 19426, United States.
authors.forename: Andrew
authors.initials: A
authors.lastname: Benowitz
authors.affiliation: GlaxoSmithKline , 1250 S. Collegeville Road, Collegeville, Pennsylvania 19426, United States.
authors.forename: Pat
authors.initials: P
authors.lastname: Brady
authors.affiliation: GlaxoSmithKline , 830 Winter Street, Waltham, Massachusetts 02451, United States.
authors.forename: LaShadric C
authors.initials: LC
authors.lastname: Grady
authors.affiliation: GlaxoSmithKline , 5 Moore Drive, Research Triangle Park, North Carolina 27009, United States.
authors.forename: Luz Helena
authors.initials: LH
authors.lastname: Kryn
authors.affiliation: GlaxoSmithKline , 1250 S. Collegeville Road, Collegeville, Pennsylvania 19426, United States.
authors.forename: David
authors.initials: D
authors.lastname: Holmes
authors.affiliation: GlaxoSmithKline , 1250 S. Collegeville Road, Collegeville, Pennsylvania 19426, United States.
authors.forename: Karen
authors.initials: K
authors.lastname: Ingraham
authors.affiliation: GlaxoSmithKline , 1250 S. Collegeville Road, Collegeville, Pennsylvania 19426, United States.
authors.forename: Qi
authors.initials: Q
authors.lastname: Jin
authors.affiliation: GlaxoSmithKline , 830 Winter Street, Waltham, Massachusetts 02451, United States.
authors.forename: Laura
authors.initials: L
authors.lastname: Pothier Kaushansky
authors.affiliation: GlaxoSmithKline , 1250 S. Collegeville Road, Collegeville, Pennsylvania 19426, United States.
authors.forename: Lynn
authors.initials: L
authors.lastname: McCloskey
authors.affiliation: GlaxoSmithKline , 830 Winter Street, Waltham, Massachusetts 02451, United States.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Messer
authors.affiliation: GlaxoSmithKline , 830 Winter Street, Waltham, Massachusetts 02451, United States.
authors.forename: Heather
authors.initials: H
authors.lastname: O'Keefe
authors.affiliation: GlaxoSmithKline , 830 Winter Street, Waltham, Massachusetts 02451, United States.
authors.forename: Amish
authors.initials: A
authors.lastname: Patel
authors.affiliation: GlaxoSmithKline , 830 Winter Street, Waltham, Massachusetts 02451, United States.
authors.forename: Alexander L
authors.initials: AL
authors.lastname: Satz
authors.affiliation: GlaxoSmithKline , 1250 S. Collegeville Road, Collegeville, Pennsylvania 19426, United States.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Sinnamon
authors.affiliation: GlaxoSmithKline , 1250 S. Collegeville Road, Collegeville, Pennsylvania 19426, United States.
authors.forename: Jessica
authors.initials: J
authors.lastname: Schneck
authors.affiliation: GlaxoSmithKline , 830 Winter Street, Waltham, Massachusetts 02451, United States.
authors.forename: Steve R
authors.initials: SR
authors.lastname: Skinner
authors.affiliation: GlaxoSmithKline , 830 Winter Street, Waltham, Massachusetts 02451, United States.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Summerfield
authors.affiliation: GlaxoSmithKline , 1250 S. Collegeville Road, Collegeville, Pennsylvania 19426, United States.
authors.forename: Amy
authors.initials: A
authors.lastname: Taylor
authors.affiliation: GlaxoSmithKline , 1250 S. Collegeville Road, Collegeville, Pennsylvania 19426, United States.
authors.forename: J David
authors.initials: JD
authors.lastname: Taylor
authors.affiliation: GlaxoSmithKline , 830 Winter Street, Waltham, Massachusetts 02451, United States.
authors.forename: Ghotas
authors.initials: G
authors.lastname: Evindar
authors.affiliation: GlaxoSmithKline , 1250 S. Collegeville Road, Collegeville, Pennsylvania 19426, United States.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Stavenger
mesh_terms: D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D015394:Molecular Structure; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000201:enzymology; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D011720:Pyrazoles; D019883:Alkyl and Aryl Transferases; C023266:undecaprenyl pyrophosphate synthetase