Antibacterial Agents That Inhibit Lipid A Biosynthesis

TLDR

Lipid A forms the outer monolayer of Gram‑negative bacteria and is essential for bacterial growth. The inhibitors are chiral hydroxamic acids with hydrophobic aromatic groups that may bind a metal in the deacetylase active site. Synthetic chiral hydroxamic acid inhibitors, with the most potent analog showing a 50 nM IC50 and 1 µg/mL MIC, kill E.

Abstract

Lipid A constitutes the outer monolayer of the outer membrane of Gram-negative bacteria and is essential for bacterial growth. Synthetic antibacterials were identified that inhibit the second enzyme (a unique deacetylase) of lipid A biosynthesis. The inhibitors are chiral hydroxamic acids bearing certain hydrophobic aromatic moieties. They may bind to a metal in the active site of the deacetylase. The most potent analog (with an inhibition constant of about 50 nM) displayed a minimal inhibitory concentration of about 1 microgram per milliliter against Escherichia coli, caused three logs of bacterial killing in 4 hours, and cured mice infected with a lethal intraperitoneal dose of E. coli.