10.1128/AAC.50.2.556-564.2006. 2006, 50(2):556. DOI: Antimicrob. Agents Chemother. Tarek S. Mansour S. Shumsky, Kristina M. K. Kutterer, Adam Gilbert and David M. Shlaes, Beth A. Rasmussen, Amedeo A. Failli, Jay Kristine Svenson, Peter J. Petersen, Pornpen Labthavikul, Krishnamurthy, Guy Singh, William Hu, David Keeney, Youjun Yang, Anatoly Severin, Rajiv Chopra, Girija Gram-Positive Bacteria Reductase (MurB) with Activity against Acetylenolpyruvylglucosamine N UDP3,5-Dioxopyrazolidines, Novel Inhibitors of

A series of pyrazolidine-3,5-dione and 5-hydroxy-1H-pyrazol-3(2H)-one inhibitors of Escherichia coli UDP-N-acetylenolpyruvyl glucosamine reductase (MurB) has been prepared. The 5-hydroxy-1H-pyrazol-3(2H)ones show low micromolar IC50 values versus E. coli MurB and submicromolar minimal inhibitory concentrations ( MIC) against Staphylococcus aureus GC 1131, Enterococcus faecalis GC 2242, Streptococcus pneumoniae GC 1894, and E. coli GC 4560 imp, a strain with increased outer membrane permeability. None of these compounds show antimicrobial activity against Candida albicans, a marker of eukaryotic toxicity. Moreover, these compounds inhibit peptidoglycan biosynthesis, as assessed by measuring the amount of soluble peptidoglycan produced by Streptococcus epidermidis upon incubation with compounds. A partial least squares projection to latent structures analysis shows that improving MurB potency and MIC values correlate with increasing lipophilicity of the C-4 substituent of the 5-hydroxy-1H-pyrazol-3(2H)-one core. Docking studies using FLO and PharmDock produced several binding orientations for these molecules in the MurB active site.