Journal
BIOCHEMISTRY
Volume 44, Issue 50, Pages 16574-16583Publisher
AMER CHEMICAL SOC
DOI: 10.1021/bi0518186
Keywords
-
Categories
Funding
- NIGMS NIH HHS [U54 GM069338, GM069338, R01 GM051310-11, GM-51310, R01 GM051310] Funding Source: Medline
Ask authors/readers for more resources
The zinc-dependent enzyme LpxC catalyzes the deacetylation of UDP-3-O-acyl-GlcNAc, the first committed step of lipid A biosynthesis. Lipid A is an essential component of the outer membranes of most Gram-negative bacteria, including Escherichia coli, Salmonella enterica, and Pseudomonas aeruginosa, making LpxC an attractive target for antibiotic design. The inhibition of LpxC by a novel N-aroyl-L-threonine hydroxamic acid (CHIR-090) from a recent patent application (International Patent WO 2004/062601 A2 to Chiron and the University of Washington) is reported here. CHIR-090 possesses remarkable antibiotic activity against both E. coli and P. aeruginosa, comparable to that of ciprofloxacin. The biological activity of CHIR-090 is explained by its inhibition of diverse LpxC orthologues at low nanomolar concentrations, including that of Aquifex aeolicus, for which structural information is available. The inhibition of A. aeolicus LpxC by CHIR-090 occurs in two steps. The first step is rapid and reversible, with a K-i of 1.0-1.7 nM, depending upon the method of assay. The second step involves the conversion of the El complex with a half-life of about a minute to a tightly bound form. The second step is functionally irreversible but does not result in the covalent modification of the enzyme, as judged by electrospray ionization mass spectrometry. CHIR-090 is the first example of a slow, tight-binding inhibitor for LpxC and may be the prototype for a new generation of LpxC inhibitors with therapeutic applicability.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available