Taxonomic group: bacteria / Proteobacteria
(Phylum: Proteobacteria)
Associated disease: infection due to Escherichia coli [ICD11:
XN6P4 
];
infection due to Salmonella enterica [ICD11:
XN5VC ];
infection due to Pseudomonas aeruginosa [ICD11:
XN5L6 ]
NCBI PubMed ID: 16342948Journal NLM ID: 0370623Publisher: American Chemical Society
Institutions: Department of Biochemistry, Duke University Medical Center, Post Office Box 3711, Durham, North Carolina 27710, and Department of Chemistry, University of Washington, Seattle, Washington 98195
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.
biosynthesis, chemistry, structural, Pseudomonas, Pseudomonas aeruginosa, form, Escherichia, Escherichia coli, acid, lipid, lipid A, complex, generation, bacteria, electrospray, ionization mass spectrometry, spectrometry, biological, Salmonella, activity, mass spectrometry, biochemistry, modification, Salmonella enterica, method, biological activity, ionization, Gram-negative bacteria, enzyme, gram negative bacteria, Gram-negative, therapeutic, inhibition, component, bound, concentration, membrane, membranes, conversion, outer membrane, assay, medical, Electrospray Ionization, electrospray-ionization, application, target, outer membranes, deacetylation, inhibitor, antibiotic, P, covalent, design, UDP-3-O-acyl-GlcNAc
Structure type: oligomer
Location inside paper: p.16575
Aglycon: lipid A
Trivial name: outer core region
Compound class: core oligosaccharide, LOS, LPS
Contained glycoepitopes: IEDB_130650,IEDB_130659
Methods: biochemical methods
Enzymes that release or process the structure: zinc-dependent LpxC enzyme
Biosynthesis and genetic data: biosynthesis data
Comments, role: Kdo-region of lippolysaccharide
Related record ID(s): 13, 829, 852, 875, 924, 6252, 6306, 6431, 7184, 8403, 10590, 23706, 24940
NCBI Taxonomy refs (TaxIDs): 562,
28901,
287Reference(s) to other database(s): GTC:G36348JQ, GlycomeDB:
5576
Show glycosyltransferases
There is only one chemically distinct structure:
Found 
report error