Exploring the UDP pocket of LpxC through amino acid analogs.
Bioorg Med Chem Lett
; 23(8): 2362-7, 2013 Apr 15.
Article
en En
| MEDLINE
| ID: mdl-23499237
ABSTRACT
Lipopolysaccharide (LPS) biosynthesis is an attractive antibacterial target as it is both conserved and essential for the survival of key pathogenic bacteria. Lipid A is the hydrophobic anchor for LPS and a key structural component of the outer membrane of Gram-negative bacteria. Lipid A biosynthesis is performed in part by a unique zinc dependent metalloamidase, LpxC (UDP-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase), which catalyzes the first non-reversible step in lipid A biosynthesis. The UDP portion of the LpxC substrate-binding pocket has been relatively unexplored. We have designed and evaluated a series of hydroxamate based inhibitors which explore the SAR of substitutions directed into the UDP pocket with a range of substituted α-amino acid based linkers. We also provide the first wild type structure of Pseudomonas aeruginosa LpxC which was utilized in the design of many of these analogs.
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Uridina Difosfato
/
Amidohidrolasas
/
Aminoácidos Cíclicos
Idioma:
En
Año:
2013
Tipo del documento:
Article