Structure based design of an in vivo active hydroxamic acid inhibitor of P. aeruginosa LpxC.
Bioorg Med Chem Lett
; 22(7): 2536-43, 2012 Apr 01.
Article
em En
| MEDLINE
| ID: mdl-22401863
ABSTRACT
Lipid A is an essential component of the Gram negative outer membrane, which protects the bacterium from attack of many antibiotics. The Lipid A biosynthesis pathway is essential for Gram negative bacterial growth and is unique to these bacteria. The first committed step in Lipid A biosynthesis is catalysis by LpxC, a zinc dependent deacetylase. We show the design of an LpxC inhibitor utilizing a robust model which directed efficient design of picomolar inhibitors. Analysis of physiochemical properties drove design to focus on an optimal lipophilicity profile. Further structure based design took advantage of a conserved water network over the active site, and with the optimal lipophilicity profile, led to an improved LpxC inhibitor with in vivo activity against wild type Pseudomonas aeruginosa.
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01-internacional
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MEDLINE
Idioma:
En
Ano de publicação:
2012
Tipo de documento:
Article