Discovery of an allosteric inhibitor binding site in 3-Oxo-acyl-ACP reductase from Pseudomonas aeruginosa.

ABSTRACT: 3-Oxo-acyl-acyl carrier protein (ACP) reductase (FabG) plays a key role in the bacterial fatty acid synthesis II system in pathogenic microorganisms, which has been recognized as a potential drug target. FabG catalyzes reduction of a 3-oxo-acyl-ACP intermediate during the elongation cycle of fatty acid biosynthesis. Here, we report gene deletion experiments that support the essentiality of this gene in P. aeruginosa and the identification of a number of small molecule FabG inhibitors with IC50 values in the nanomolar to low micromolar range and good physicochemical properties. Structural characterization of 16 FabG-inhibitor complexes by X-ray crystallography revealed that the compounds bind at a novel allosteric site located at the FabG subunit-subunit interface. Inhibitor binding relies

SUBMITTER: Cukier CD 

PROVIDER: S-EPMC3833349 | biostudies-literature | 2013 Nov

REPOSITORIES: biostudies-literature