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.
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.


CONCLUSIONS
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.
Cuny
Gregory D
GD
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
D000581:Amidohydrolases / Q000037:antagonists & inhibitors*; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D016503:Drug Delivery Systems; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006090:Gram-Negative Bacteria / Q000187:drug effects; D016905:Gram-Negative Bacterial Infections / Q000188:drug therapy* / Q000503:physiopathology; D006801:Humans; D008050:Lipid A / Q000096:biosynthesis; D010330:Patents as Topic
D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D008050:Lipid A; D000581:Amidohydrolases; C097307:UDP-3-O-acyl-N-acetylglucosamine deacetylase