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J. Biol. Chem., Vol. 282, Issue 7, 4437-4446, February 16, 2007

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Fatty Acyl Benzamido Antibacterials Based on Inhibition of DnaK-catalyzed Protein Folding^*

Markus Liebscher, Günther Jahreis, Christian Lücke, Susanne Grabley, Satish Raina^¶, and Cordelia Schiene-Fischer¹

From the Max Planck Research Unit for Enzymology of Protein Folding, Weinbergweg 22, 06120 Halle/Saale, Germany, the Leibniz Institute for Natural Product Research and Infection Biology, Hans Knöll Institute, 07745 Jena, Germany, and the ^¶Departement de Biochimie Medicale, Centre Medical Universitaire, Universite de Geneve, 1 Rue Michel Servet, 1211 Geneva 4, Switzerland

We have reported that the hsp70 chaperone DnaK from Escherichia coli might assist protein folding by catalyzing the cis/trans isomerization of secondary amide peptide bonds in unfolded or partially folded proteins. In this study a series of fatty acylated benzamido inhibitors of the cis/trans isomerase activity of DnaK was developed and tested for antibacterial effects in E. coli MC4100 cells. N-[Tetradecanoyl-(4-aminomethylbenzoyl)]-L-asparagine is the most effective antibacterial with a minimal inhibitory concentration of 100 ± 20 µg/ml. The compounds were shown to compete with fluorophore-labeled ³²-derived peptide for the peptide binding site of DnaK and to increase the fraction of aggregated proteins in heat-shocked bacteria. Despite its inability to serve as a folding helper in vivo a DnaK-inhibitor complex was still able to sequester an unfolded protein in vitro. Structure activity relationships revealed a distinct dependence of DnaK-assisted refolding of luciferase on the fatty acyl chain length, whereas the minimal inhibitory concentration was most sensitive to the structural nature of the benzamido core. We conclude that the isomerase activity of DnaK is a major survival factor in the heat shock response of bacteria and that small molecule inhibitors can lead to functional inactivation of DnaK and thus will display antibacterial activity.

Received for publication, August 11, 2006 , and in revised form, December 5, 2006.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental HPLC, mass spectrometry, and ¹H NMR data for compounds 1–18.

¹ To whom correspondence should be addressed: Tel.: 49-345-552-2809; Fax: 49-345-551-1972; E-mail: schiene{at}enzyme-halle.mpg.de.

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