Structure based design of an in vivo active hydroxamic acid inhibitor of P. aeruginosa LpxC.

Autor: Warmus JS; Department of Chemistry, Pfizer Global Research and Development, Ann Arbor, MI 48105, USA. Joseph.Warmus@Pfizer.com, Quinn CL, Taylor C, Murphy ST, Johnson TA, Limberakis C, Ortwine D, Bronstein J, Pagano P, Knafels JD, Lightle S, Mochalkin I, Brideau R, Podoll T
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2012 Apr 01; Vol. 22 (7), pp. 2536-43. Date of Electronic Publication: 2012 Feb 16.
DOI: 10.1016/j.bmcl.2012.01.140
Abstrakt: 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.
(Copyright © 2012 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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