A new class of UDP-3-O-(R-3-hydroxymyristol)-N-acetylglucosamine deacetylase (LpxC) inhibitors for the treatment of Gram-negative infections: PCT application WO 2008027466

Abstract

Background: Human infections due to Gram-negative bacteria cause significant morbidity and mortality. Identification of new strategies, molecular targets, and agents for the treatment of Gram-negative bacterial infections are needed urgently. Lipid A is a necessary component of the lipopolysaccharide-containing outer membrane of Gram-negative bacteria. The zinc-dependent hydrolase UDP-3-O-(R-3-hydroxymyristol)-N-acetylglucosamine deacetylase (LpxC) involved in the first committed step in the biosynthetic pathway of lipid A has no sequence homology to any known mammalian enzymes and has emerged as an attractive Gram-negative antibacterial molecular target. Most previously described LpxC inhibitors contain a hydroxamic acid, which can lead to low specificity vs. other metal-dependent enzymes and can consequently result in unwanted side effects. Objective: This review examines a new reported class of nonhydroxamic LpxC inhibitors for the treatment of Gram-negative infections. Methods: The new class of inhibitor is compared with several previously reported LpxC inhibitors. Conclusion: The LpxC inhibitors disclosed in PCT application WO 2008027466 contain hydantoins in place of the hydroxamic acids commonly found in most previously described inhibitors. These molecules could represent a means of treating Gram-negative infections via a more selective inhibition of LpxC.