PMID:16436710
| Citation |
Yang, Y, Severin, A, Chopra, R, Krishnamurthy, G, Singh, G, Hu, W, Keeney, D, Svenson, K, Petersen, PJ, Labthavikul, P, Shlaes, DM, Rasmussen, BA, Failli, AA, Shumsky, JS, Kutterer, KM, Gilbert, A and Mansour, TS (2006) 3,5-dioxopyrazolidines, novel inhibitors of UDP-N- acetylenolpyruvylglucosamine reductase (MurB) with activity against gram-positive bacteria. Antimicrob. Agents Chemother. 50:556-64 |
|---|---|
| Abstract |
A series of 3,5-dioxopyrazolidines was identified as novel inhibitors of UDP-N-acetylenolpyruvylglucosamine reductase (MurB). Compounds 1 to 3, which are 1,2-bis(4-chlorophenyl)-3,5-dioxopyrazolidine-4-carboxamides, inhibited Escherichia coli MurB, Staphyloccocus aureus MurB, and E. coli MurA with 50% inhibitory concentrations (IC50s) in the range of 4.1 to 6.8 microM, 4.3 to 10.3 microM, and 6.8 to 29.4 microM, respectively. Compound 4, a C-4-unsubstituted 1,2-bis(3,4-dichlorophenyl)-3,5-dioxopyrazolidine, showed moderate inhibitory activity against E. coli MurB, S. aureus MurB, and E. coli MurC (IC50s, 24.5 to 35 microM). A fluorescence-binding assay indicated tight binding of compound 3 with E. coli MurB, giving a dissociation constant of 260 nM. Structural characterization of E. coli MurB was undertaken, and the crystal structure of a complex with compound 4 was obtained at 2.4 A resolution. The crystal structure indicated the binding of a compound at the active site of MurB and specific interactions with active-site residues and the bound flavin adenine dinucleotide cofactor. Peptidoglycan biosynthesis studies using a strain of Staphylococcus epidermidis revealed reduced peptidoglycan biosynthesis upon incubation with 3,5-dioxopyrazolidines, with IC50s of 0.39 to 11.1 microM. Antibacterial activity was observed for compounds 1 to 3 (MICs, 0.25 to 16 microg/ml) and 4 (MICs, 4 to 8 microg/ml) against gram-positive bacteria including methicillin-resistant S. aureus, vancomycin-resistant Enterococcus faecalis, and penicillin-resistant Streptococcus pneumoniae. |
| Links |
PubMed PMC1366903 Online version:10.1128/AAC.50.2.556-564.2006 |
| Keywords |
Anti-Bacterial Agents/pharmacology; Carbohydrate Dehydrogenases/antagonists & inhibitors; Carbohydrate Dehydrogenases/chemistry; Carbohydrate Dehydrogenases/metabolism; Crystallography; Fluorescence; Gram-Positive Bacteria/drug effects; Microbial Sensitivity Tests; Peptidoglycan/biosynthesis; Protein Binding; Pyrazoles/pharmacology |
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