Inhibition of the antibacterial target UDP-(3-O-acyl)-N-acetylglucosamine deacetylase (LpxC): isoxazoline zinc amidase inhibitors bearing diverse metal binding groups.
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.
Pirrung
Michael C
MC
Department of Chemistry, Levine Science Research Center, Box 90317, Duke University, Durham, NC 27708-0317, USA. pirrung@chem.duke.edu
Tumey
L Nathan
LN
Raetz
Christian R H
CR
Jackman
Jane E
JE
Snehalatha
Karnem
K
McClerren
Amanda L
AL
Fierke
Carol A
CA
Gantt
Stephanie L
SL
Rusche
Kristin M
KM
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*
D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; D007555:Isoxazoles; D000581:Amidohydrolases; C097307:UDP-3-O-acyl-N-acetylglucosamine deacetylase; D015032:Zinc