l-161240 and Escherichia-coli-Infections

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.

Topics: Amidohydrolases; Animals; Anti-Bacterial Agents; Binding Sites; Escherichia coli; Escherichia coli Infections; Gram-Negative Bacteria; Hydroxamic Acids; Lipid A; Mice; Microbial Sensitivity Tests; Oxazoles; Pseudomonas; Serratia; Stereoisomerism; Structure-Activity Relationship