Fragment-Based Discovery of Novel Non-Hydroxamate LpxC Inhibitors with Antibacterial Activity

UDP-3-O-acyl-N-acetylglucosamine
deacetylase (LpxC) is a zinc metalloenzyme that catalyzes the first
committed step in the biosynthesis of Lipid A, an essential component
of the cell envelope of Gram-negative bacteria. The most advanced,
disclosed LpxC inhibitors showing antibacterial activity coordinate
zinc through a hydroxamate moiety with concerns about binding to other
metalloenzymes. Here, we describe the discovery, optimization, and
efficacy of two series of compounds derived from fragments with differing
modes of zinc chelation. A series was evolved from a fragment where
a glycine moiety complexes zinc, which achieved low nanomolar potency
in an enzyme functional assay but poor antibacterial activity on cell
cultures. A second series was based on a fragment that chelated zinc
through an imidazole moiety. Structure-guided design led to a 2-(1S-hydroxyethyl)-imidazole derivative exhibiting low nanomolar
inhibition of LpxC and a minimum inhibitory concentration (MIC) of
4 μg/mL against Pseudomonas aeruginosa, which is little affected by the presence of albumin.