Uridine-based inhibitors as new leads for antibiotics targeting Escherichia coli LpxC.
Journal Article (Journal Article)
The UDP-3-O-(R-3-hydroxyacyl)-N-acetylglucosamine deacetylase LpxC catalyzes the committed reaction of lipid A (endotoxin) biosynthesis in Gram-negative bacteria and is a validated antibiotic target. Although several previously described compounds bind to the unique acyl chain binding passage of LpxC with high affinity, strategies to target the enzyme's UDP-binding site have not been reported. Here the identification of a series of uridine-based LpxC inhibitors is presented. The most potent examined, 1-68A, is a pH-dependent, two-step, covalent inhibitor of Escherichia coli LpxC that competes with UDP to bind the enzyme in the first step of inhibition. Compound 1-68A exhibits a K(I) of 54 muM and a maximal rate of inactivation (k(inact)) of 1.7 min(-1) at pH 7.4. Dithiothreitol, glutathione and the C207A mutant of E. coli LpxC prevent the formation of a covalent complex by 1-68A, suggesting a role for Cys-207 in inhibition. The inhibitory activity of 1-68A and a panel of synthetic analogues identified moieties necessary for inhibition. 1-68A and a 2-dehydroxy analogue, 1-68Aa, inhibit several purified LpxC orthologues. These compounds may provide new scaffolds for extension of existing LpxC-inhibiting antibiotics to target the UDP binding pocket.
Full Text
Duke Authors
Cited Authors
- Barb, AW; Leavy, TM; Robins, LI; Guan, Z; Six, DA; Zhou, P; Hangauer, MJ; Bertozzi, CR; Raetz, CRH
Published Date
- April 14, 2009
Published In
Volume / Issue
- 48 / 14
Start / End Page
- 3068 - 3077
PubMed ID
- 19256534
Pubmed Central ID
- PMC2709817
Electronic International Standard Serial Number (EISSN)
- 1520-4995
Digital Object Identifier (DOI)
- 10.1021/bi900167q
Language
- eng
Conference Location
- United States