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Expert Opin Ther Pat. 2009 Jun;19(6):893-9. doi: 10.1517/13543770902766829.

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.

Author information

1
Brigham & Women's Hospital, Harvard Medical School, Partners Center for Drug Discovery, Laboratory for Drug Discovery in Neurodegeneration, 65 Landsdowne Street, Cambridge, MA 02139, USA. gcuny@rics.bwh.harvard.edu

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.

PMID:
19473108
DOI:
10.1517/13543770902766829
[Indexed for MEDLINE]

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