Mapping the Active Site of the Bacterial Enzyme LpxC Using Novel Carbohydrate‐Based Hydroxamic Acid Inhibitors*

* In memory of Jacques H. van Boom.

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.

* In memory of Jacques H. van Boom.

Keywords:

• Carbohydrate analog
• Enzyme inhibitor
• Hydroxamic acid
• Deacetylase

Acknowledgement

This work is supported by the Natural Science and Engineering Research Council of Canada (O.H) and the NIH (grant GM‐51310 to C.R.H.R). X.L. is the recipient of a graduate scholarship in Carbohydrate Chemistry from the Alberta Research Council. The authors thank Prof. Pei Zhou for helpful discussions.

Notes

* In memory of Jacques H. van Boom.