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Abstract
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. Nα-[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 σ32-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.
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Authors (6)
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Markus Liebscher
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Günther Jahreis
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Christian Lücke
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Susanne Grabley
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Cordelia Schiene-Fischer
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Full text
- Publication version
- Accepted or Published Version
- DOI:
- Digital Object Identifier (open in new tab) 10.1074/jbc.M607667200
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- Category:
- Articles
- Type:
- artykuły w czasopismach
- Published in:
-
JOURNAL OF BIOLOGICAL CHEMISTRY
no. 282,
pages 4437 - 4446,
ISSN: 0021-9258 - Language:
- English
- Publication year:
- 2007
- Bibliographic description:
- Liebscher M., Jahreis G., Lücke C., Grabley S., Raina S., Schiene-Fischer C.: Fatty acyl benzamido antibacterials based on inhibition of DnaK-catalyzed protein folding// JOURNAL OF BIOLOGICAL CHEMISTRY -Vol. 282,iss. 7 (2007), s.4437-4446
- DOI:
- Digital Object Identifier (open in new tab) 10.1074/jbc.m607667200
- Verified by:
- Gdańsk University of Technology
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