In vitro analysis of novel inhibitors for Escherichia coli MurA (582.4)

Abstract

The widespread of use of antibiotics to treat bacterial infection has selected for antibiotic resistant strains of bacteria. Fosfomycin is an example of a broad spectrum antibiotic that has become less effective because of increased bacterial resistance. Fosfomycin inhibits synthesis of peptidoglycan, a structural component of the bacterial cell wall. Fosfomycin covalently binds to the phosphoenolpyruvate binding site of the enzyme MurA, an essential enzyme in the peptidoglycan synthesis pathway. MurA catalyzes the addition of the enolpyruvate to UDP‐N‐acetylglucosamine. The additional product, an inorganic phosphate, is detected by the indicator, malachite green. Muzyka, et al. has identified putative inhibitors through DOCK and AMBER studies. IC50 values have been determined for BCB33b and VS5 of these molecules. Additional molecules with similar functional groups are being synthesized and evaluated as putative inhibitors. The site of inhibitor binding will be determined with in silico studies and site‐directed mutagenesis.Grant Funding Source: Centre College Faculty Development Fund and the Alcock Interdisciplinary Fund