title: Structure-based discovery of LpxC inhibitors.
abstract: The emergence and spread of multidrug-resistant (MDR) Gram negative bacteria presents a serious threat for public health. Novel antimicrobials that could overcome the resistance problems are urgently needed. UDP-3-O-(R-3-hydroxymyristol)-N-acetylglucosamine deacetylase (LpxC) is a cytosolic zinc-based deacetylase that catalyzes the first committed step in the biosynthesis of lipid A, which is essential for the survival of Gram-negative bacteria. Our efforts toward the discovery of novel LpxC inhibitors are presented herein.
authors.affiliation: Cubist Pharmaceuticals Inc., 65 Hayden Avenue, Lexington, MA 02421, USA. Electronic address: jackzhang49@yahoo.com.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Cubist Pharmaceuticals Inc., 65 Hayden Avenue, Lexington, MA 02421, USA.
authors.forename: Audrey
authors.initials: A
authors.lastname: Chan
authors.affiliation: Cubist Pharmaceuticals Inc., 65 Hayden Avenue, Lexington, MA 02421, USA.
authors.forename: Blaise
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authors.lastname: Lippa
authors.affiliation: Cubist Pharmaceuticals Inc., 65 Hayden Avenue, Lexington, MA 02421, USA.
authors.forename: Jason B
authors.initials: JB
authors.lastname: Cross
authors.affiliation: Cubist Pharmaceuticals Inc., 65 Hayden Avenue, Lexington, MA 02421, USA.
authors.forename: Christopher
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authors.lastname: Liu
authors.affiliation: Cubist Pharmaceuticals Inc., 65 Hayden Avenue, Lexington, MA 02421, USA.
authors.forename: Ning
authors.initials: N
authors.lastname: Yin
authors.affiliation: Cubist Pharmaceuticals Inc., 65 Hayden Avenue, Lexington, MA 02421, USA.
authors.forename: Jan Antoinette C
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authors.lastname: Romero
authors.affiliation: Cubist Pharmaceuticals Inc., 65 Hayden Avenue, Lexington, MA 02421, USA.
authors.forename: Jonathan
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authors.lastname: Lawrence
authors.affiliation: Cubist Pharmaceuticals Inc., 65 Hayden Avenue, Lexington, MA 02421, USA.
authors.forename: Ryan
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authors.lastname: Heney
authors.affiliation: Cubist Pharmaceuticals Inc., 65 Hayden Avenue, Lexington, MA 02421, USA.
authors.forename: Prudencio
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authors.lastname: Herradura
authors.affiliation: Cubist Pharmaceuticals Inc., 65 Hayden Avenue, Lexington, MA 02421, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Goss
authors.affiliation: Cubist Pharmaceuticals Inc., 65 Hayden Avenue, Lexington, MA 02421, USA.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Clark
authors.affiliation: Cubist Pharmaceuticals Inc., 65 Hayden Avenue, Lexington, MA 02421, USA.
authors.forename: Cassandra
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authors.lastname: Abel
authors.affiliation: Cubist Pharmaceuticals Inc., 65 Hayden Avenue, Lexington, MA 02421, USA.
authors.forename: Yanzhi
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authors.lastname: Zhang
authors.affiliation: Cubist Pharmaceuticals Inc., 65 Hayden Avenue, Lexington, MA 02421, USA.
authors.forename: Katherine M
authors.initials: KM
authors.lastname: Poutsiaka
authors.affiliation: Cubist Pharmaceuticals Inc., 65 Hayden Avenue, Lexington, MA 02421, USA.
authors.forename: Felix
authors.initials: F
authors.lastname: Epie
authors.affiliation: Cubist Pharmaceuticals Inc., 65 Hayden Avenue, Lexington, MA 02421, USA.
authors.forename: Mary
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authors.lastname: Conrad
authors.affiliation: Cubist Pharmaceuticals Inc., 65 Hayden Avenue, Lexington, MA 02421, USA.
authors.forename: Azard
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authors.lastname: Mahamoon
authors.affiliation: Cubist Pharmaceuticals Inc., 65 Hayden Avenue, Lexington, MA 02421, USA.
authors.forename: Kien
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authors.lastname: Nguyen
authors.affiliation: Cubist Pharmaceuticals Inc., 65 Hayden Avenue, Lexington, MA 02421, USA.
authors.forename: Ajit
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authors.lastname: Chavan
authors.affiliation: Cubist Pharmaceuticals Inc., 65 Hayden Avenue, Lexington, MA 02421, USA.
authors.forename: Edward
authors.initials: E
authors.lastname: Clark
authors.affiliation: Cubist Pharmaceuticals Inc., 65 Hayden Avenue, Lexington, MA 02421, USA.
authors.forename: Tong-Chuan
authors.initials: TC
authors.lastname: Li
authors.affiliation: Evotec UK, Ltd., 114 Innovation Drive, Milton Park, Abingdon, Oxfordshire OX14 4RZ, UK.
authors.forename: Robert K
authors.initials: RK
authors.lastname: Cheng
authors.affiliation: Evotec UK, Ltd., 114 Innovation Drive, Milton Park, Abingdon, Oxfordshire OX14 4RZ, UK.
authors.forename: Michael
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authors.lastname: Wood
authors.affiliation: Evotec UK, Ltd., 114 Innovation Drive, Milton Park, Abingdon, Oxfordshire OX14 4RZ, UK.
authors.forename: Ole A
authors.initials: OA
authors.lastname: Andersen
authors.affiliation: Evotec UK, Ltd., 114 Innovation Drive, Milton Park, Abingdon, Oxfordshire OX14 4RZ, UK.
authors.forename: Mark
authors.initials: M
authors.lastname: Brooks
authors.affiliation: Evotec UK, Ltd., 114 Innovation Drive, Milton Park, Abingdon, Oxfordshire OX14 4RZ, UK.
authors.forename: Jason
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authors.lastname: Kwong
authors.affiliation: Evotec UK, Ltd., 114 Innovation Drive, Milton Park, Abingdon, Oxfordshire OX14 4RZ, UK.
authors.forename: John
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authors.lastname: Barker
authors.affiliation: Cubist Pharmaceuticals Inc., 65 Hayden Avenue, Lexington, MA 02421, USA.
authors.forename: Ian Barrie
authors.initials: IB
authors.lastname: Parr
authors.affiliation: Cubist Pharmaceuticals Inc., 65 Hayden Avenue, Lexington, MA 02421, USA.
authors.forename: Yugui
authors.initials: Y
authors.lastname: Gu
authors.affiliation: Cubist Pharmaceuticals Inc., 65 Hayden Avenue, Lexington, MA 02421, USA.
authors.forename: M Dominic
authors.initials: MD
authors.lastname: Ryan
authors.affiliation: Cubist Pharmaceuticals Inc., 65 Hayden Avenue, Lexington, MA 02421, USA.
authors.forename: Scott
authors.initials: S
authors.lastname: Coleman
authors.affiliation: Cubist Pharmaceuticals Inc., 65 Hayden Avenue, Lexington, MA 02421, USA.
authors.forename: Chester A
authors.initials: CA
authors.lastname: Metcalf
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology*; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D006090:Gram-Negative Bacteria / Q000187:drug effects* / Q000201:enzymology*; D016905:Gram-Negative Bacterial Infections / Q000188:drug therapy; D006801:Humans; D062105:Molecular Docking Simulation
chemical_list: D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D000581:Amidohydrolases; C023079:N-acetylglucosamine deacetylase
keywords: Acinetobacter baumannii; Antibacterial; Escherichia coli; Klebsiella pneumonia; LpxC; Pseudomonas aeruginosa