title: Inhibition of the antibacterial target UDP-(3-O-acyl)-N-acetylglucosamine deacetylase (LpxC): isoxazoline zinc amidase inhibitors bearing diverse metal binding groups.
abstract: UDP-3-O-[R-3-hydroxymyristoyl]-GlcNAc deacetylase (LpxC) is a zinc amidase that catalyzes the second step of lipid A biosynthesis in Gram negative bacteria. Known inhibitors of this enzyme are oxazolines incorporating a hydroxamic acid at the 4-position, which is believed to coordinate to the single essential zinc ion. A new structural class of inhibitors was designed to incorporate a more stable and more synthetically versatile isoxazoline core. The synthetic versatility of the isoxazoline allowed for a broad study of metal binding groups. Nine of 17 isoxazolines, each incorporating a different potential metal binding functional group, were found to exhibit enzyme inhibitory activity, including one that is more active than the corresponding hydroxamic acid. Additionally, a designed affinity label inhibits LpxC in a time-dependent manner.
authors.affiliation: Department of Chemistry, Levine Science Research Center, Box 90317, Duke University, Durham, NC 27708-0317, USA. pirrung@chem.duke.edu
authors.forename: Michael C
authors.initials: MC
authors.lastname: Pirrung
authors.forename: L Nathan
authors.initials: LN
authors.lastname: Tumey
authors.forename: Christian R H
authors.initials: CR
authors.lastname: Raetz
authors.forename: Jane E
authors.initials: JE
authors.lastname: Jackman
authors.forename: Karnem
authors.initials: K
authors.lastname: Snehalatha
authors.forename: Amanda L
authors.initials: AL
authors.lastname: McClerren
authors.forename: Carol A
authors.initials: CA
authors.lastname: Fierke
authors.forename: Stephanie L
authors.initials: SL
authors.lastname: Gantt
authors.forename: Kristin M
authors.initials: KM
authors.lastname: Rusche
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015169:Colony Count, Microbial; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004926:Escherichia coli / Q000187:drug effects; D006877:Hydroxamic Acids / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D007555:Isoxazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D013329:Structure-Activity Relationship; D015032:Zinc / Q000378:metabolism*
chemical_list: D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; D007555:Isoxazoles; D000581:Amidohydrolases; C097307:UDP-3-O-acyl-N-acetylglucosamine deacetylase; D015032:Zinc