Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
50
pubmed:dateCreated
2005-12-13
pubmed:abstractText
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 EI 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.
pubmed:grant
pubmed:commentsCorrections
http://linkedlifedata.com/resource/pubmed/commentcorrection/16342948-10026271, http://linkedlifedata.com/resource/pubmed/commentcorrection/16342948-10103173, http://linkedlifedata.com/resource/pubmed/commentcorrection/16342948-10753902, http://linkedlifedata.com/resource/pubmed/commentcorrection/16342948-10984043, http://linkedlifedata.com/resource/pubmed/commentcorrection/16342948-11148046, http://linkedlifedata.com/resource/pubmed/commentcorrection/16342948-12019092, http://linkedlifedata.com/resource/pubmed/commentcorrection/16342948-12045108, http://linkedlifedata.com/resource/pubmed/commentcorrection/16342948-12086497, http://linkedlifedata.com/resource/pubmed/commentcorrection/16342948-12171558, http://linkedlifedata.com/resource/pubmed/commentcorrection/16342948-12213077, http://linkedlifedata.com/resource/pubmed/commentcorrection/16342948-12324252, http://linkedlifedata.com/resource/pubmed/commentcorrection/16342948-12354551, http://linkedlifedata.com/resource/pubmed/commentcorrection/16342948-12540854, http://linkedlifedata.com/resource/pubmed/commentcorrection/16342948-12568618, http://linkedlifedata.com/resource/pubmed/commentcorrection/16342948-12583763, http://linkedlifedata.com/resource/pubmed/commentcorrection/16342948-12702699, http://linkedlifedata.com/resource/pubmed/commentcorrection/16342948-12819349, http://linkedlifedata.com/resource/pubmed/commentcorrection/16342948-12833153, http://linkedlifedata.com/resource/pubmed/commentcorrection/16342948-14559095, http://linkedlifedata.com/resource/pubmed/commentcorrection/16342948-15040181, http://linkedlifedata.com/resource/pubmed/commentcorrection/16342948-15090508, http://linkedlifedata.com/resource/pubmed/commentcorrection/16342948-1509257, http://linkedlifedata.com/resource/pubmed/commentcorrection/16342948-15581567, http://linkedlifedata.com/resource/pubmed/commentcorrection/16342948-15667204, http://linkedlifedata.com/resource/pubmed/commentcorrection/16342948-15667205, http://linkedlifedata.com/resource/pubmed/commentcorrection/16342948-15705580, http://linkedlifedata.com/resource/pubmed/commentcorrection/16342948-15823014, http://linkedlifedata.com/resource/pubmed/commentcorrection/16342948-2824434, http://linkedlifedata.com/resource/pubmed/commentcorrection/16342948-2994404, http://linkedlifedata.com/resource/pubmed/commentcorrection/16342948-3281418, http://linkedlifedata.com/resource/pubmed/commentcorrection/16342948-3288280, http://linkedlifedata.com/resource/pubmed/commentcorrection/16342948-7317361, http://linkedlifedata.com/resource/pubmed/commentcorrection/16342948-8366124, http://linkedlifedata.com/resource/pubmed/commentcorrection/16342948-8530464, http://linkedlifedata.com/resource/pubmed/commentcorrection/16342948-8875939, http://linkedlifedata.com/resource/pubmed/commentcorrection/16342948-9278503, http://linkedlifedata.com/resource/pubmed/commentcorrection/16342948-9537320, http://linkedlifedata.com/resource/pubmed/commentcorrection/16342948-9565550
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Dec
pubmed:issn
0006-2960
pubmed:author
pubmed:issnType
Print
pubmed:day
20
pubmed:volume
44
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
16574-83
pubmed:dateRevised
2011-4-25
pubmed:meshHeading
pubmed:year
2005
pubmed:articleTitle
A slow, tight-binding inhibitor of the zinc-dependent deacetylase LpxC of lipid A biosynthesis with antibiotic activity comparable to ciprofloxacin.
pubmed:affiliation
Department of Biochemistry, Duke University Medical Center, Post Office Box 3711, Durham, North Carolina 27710, USA.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural