Identification and Characterization of New Inhibitors of the Escherichia coli MurA Enzyme (original) (raw)

2001, Antimicrobial Agents and Chemotherapy

The bacterial enzyme MurA catalyzes the transfer of enolpyruvate from phosphoenolpyruvate (PEP) to uridine diphospho- N -acetylglucosamine (UNAG), which is the first committed step of bacterial cell wall biosynthesis. From high-throughput screening of a chemical library, three novel inhibitors of the Escherichia coli MurA enzyme were identified: the cyclic disulfide RWJ-3981, the purine analog RWJ-140998, and the pyrazolopyrimidine RWJ-110192. When MurA was preincubated with inhibitor, followed by addition of UNAG and PEP, the 50% inhibitory concentrations (IC 50 s) were 0.2 to 0.9 μM, compared to 8.8 μM for the known MurA inhibitor, fosfomycin. The three compounds exhibited MICs of 4 to 32 μg/ml against Staphylococcus aureus ; however, the inhibition of DNA, RNA, and protein synthesis in addition to peptidoglycan synthesis by all three inhibitors indicated that antibacterial activity was not due specifically to MurA inhibition. The presence of UNAG during the MurA and inhibitor pre...