Progress towards the characterization of a novel substrate-analog inhibitor of UDP-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase
In 2008, the United States spent several billion dollars on health care costs associated only with multi-drug resistant bacteria, which are organisms that have resistance to three or more antimicrobial classes. The prevalence of these microbes have increased rapidly over the past fifteen years mainly due to the over-exposure of antibiotics and patient-to-patient contact in hospital settings. Multi-drug resistant Gram-negative bacteria pose a particularly serious health threat due to the presence of heteropolysaccharide chains extending from the cell walls. These chains, known as lipopolysaccharide, act as a protective barrier by preventing antibiotics and other immune responses from penetrating the cell. Lipid A is the component of lipopolysaccharide that anchors the carbohydrate chain to the cell membrane and is thus necessary for the virulence and survival of the cell. The goal of this Independent Study is to characterize a novel-substrate analog inhibitor of the enzyme UDP-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase, or LpxC. LpxC catalyzes the first committed step of the lipid A biosynthesis pathway and is highly conserved throughout all Gram-negative species. The structure of the novel inhibitor is nearly identical to the carbohydrate domain of the substrate with the exception of an additional hydroxamate group that acts as the inhibitory motif. It is hypothesized that the natural specificity of LpxC for its substrate can be exploited in order to design an inhibitor that effectively binds and blocks the catalytic function of LpxC. If this hypothesis is correct and the novel inhibitor effectively inhibits LpxC, this could give rise to the development of more substrate-analog compounds, hopefully resulting in the design of a drug that successfully treats Gram-negative bacterial infections.
© Copyright 2012 Emily Christine Linville