Exploring the UDP pocket of LpxC through amino acid analogs

被引：23

作者：

Hale, Michael R. ^{[1
]}

Hill, Pamela ^{[1
]}

Lahiri, Sushmita ^{[1
]}

Miller, Matthew D. ^{[1
]}

Ross, Philip ^{[1
]}

Alm, Richard ^{[1
]}

Gao, Ning ^{[1
]}

Kutschke, Amy ^{[1
]}

Johnstone, Michele ^{[1
]}

Prince, Bryan ^{[1
]}

Thresher, Jason ^{[1
]}

Yang, Wei ^{[1
]}

机构：

[1] AstraZeneca R&D Boston, Infect Innovat Med Unit, Waltham, MA 02451 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2013年 / 23卷 / 08期

关键词：

LpxC; Inhibitor; Antibiotic; Hydroxamate; GRAM-NEGATIVE BACTERIA; N-ACETYLGLUCOSAMINE ACYLTRANSFERASE; ENDOTOXIN BIOSYNTHESIS; DEPENDENT DEACETYLASE; ANTIBACTERIAL AGENTS; CRYSTAL-STRUCTURE; ESCHERICHIA-COLI; OUTER-MEMBRANE; INHIBITOR; BINDING;

D O I：

10.1016/j.bmcl.2013.02.055

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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 alpha-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. (C) 2013 Elsevier Ltd. All rights reserved.

引用

页码：2362 / 2367

页数：6

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