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Antimicrobial Agents and Chemotherapy, February 2006, p. 556-564, Vol. 50, No. 2
0066-4804/06/$08.00+0     doi:10.1128/AAC.50.2.556-564.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

3,5-Dioxopyrazolidines, Novel Inhibitors of UDP-N- Acetylenolpyruvylglucosamine Reductase (MurB) with Activity against Gram-Positive Bacteria

Youjun Yang, Anatoly Severin, Rajiv Chopra, Girija Krishnamurthy, Guy Singh, William Hu, David Keeney, Kristine Svenson, Peter J. Petersen, Pornpen Labthavikul, David M. Shlaes, Beth A. Rasmussen,^* Amedeo A. Failli, Jay S. Shumsky, Kristina M. K. Kutterer, Adam Gilbert, and Tarek S. Mansour

Wyeth Research, 401 N. Middleton Rd., Pearl River, New York 10965, and Wyeth Research, CN 8000, Princeton, New Jersey 08543

Received 4 August 2005/ Returned for modification 22 August 2005/ Accepted 16 October 2005

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 µM, 4.3 to 10.3 µM, and 6.8 to 29.4 µM, 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 µM). 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 Å 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 µM. Antibacterial activity was observed for compounds 1 to 3 (MICs, 0.25 to 16 µg/ml) and 4 (MICs, 4 to 8 µg/ml) against gram-positive bacteria including methicillin-resistant S. aureus, vancomycin-resistant Enterococcus faecalis, and penicillin-resistant Streptococcus pneumoniae.

Present address: Avon Products Inc., Suffern, NY 10901.

Present address: New York University, New York, NY 10016.

Present address: Idenix Pharmaceuticals, Cambridge, MA 02140.

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