Mapping the active site of the bacterial enzyme LpxC using novel carbohydrate-based hydroxamic acid inhibitors

Abstract

LpxC (UDP-3-O-(R-3-hydroxymyristoyl)-GlcNAc deacetylase), an enzyme involved in the biosynthesis of lipid A, is crucial for the growth of Gram-negative bacteria. This enzyme has accordingly been identified as a potential target for the development of novel antibiotics against Gram-negative bacteria. The carbohydrate-derived hydroxamic acid 1 (1,5-anhydro-2-C- (carboxymethyl N-hydroxyamide)-2-deoxy-3-O-myristoyl-D-glucitol) was previously shown to exhibit a wide spectrum of inhibitory activity against LpxC enzymes. Here we describe the preparation of seven analogs of 1 and their enzymatic evaluation. Two of the hydroxyl groups (OH-3 and 6) of the GlcNAc residue were found to be involved in the binding interaction, and there is an important hydrophobic interaction in the vicinity O-3 position with the enzyme that recognizes aromatic as well as aliphatic substituents. Copyright © Taylor & Francis, Inc.