A Simple Fragment of Cyclic Acyldepsipeptides Is Necessary and Sufficient for ClpP Activation and Antibacterial Activity
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Author(s)
Carney, Daniel W.
Compton, Corey L.
Stevens, Julia P.
Sello, Jason K.
Schmitz, Karl Robert
Sauer, Robert T.
Date Issued
October 2014
Journal
ChemBioChem
Publisher
Wiley Blackwell
Citation
Carney, Daniel W., Corey L. Compton, Karl R. Schmitz, Julia P. Stevens, Robert T. Sauer, and Jason K. Sello. “A Simple Fragment of Cyclic Acyldepsipeptides Is Necessary and Sufficient for ClpP Activation and Antibacterial Activity.” ChemBioChem 15, no. 15 (September 11, 2014): 2216–2220. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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Author's final manuscript
Abstract
The development of new antibacterial agents, particularly those with unique biological targets, is essential to keep pace with the inevitable emergence of drug resistance in pathogenic bacteria. We identified the minimal structural component of the cyclic acyldepsipeptide (ADEP) antibiotics that exhibits antibacterial activity. We found that N-acyldifluorophenylalanine fragments function via the same mechanism of action as ADEPs, as evidenced by the requirement of ClpP for the fragments' antibacterial activity, the ability of fragments to activate Bacillus subtilis ClpP in vitro, and the capacity of an N-acyldifluorophenylalanine affinity matrix to capture ClpP from B. subtilis cell lysates. N-acyldifluorophenylalanine fragments are much simpler in structure than the full ADEPs and are also highly amenable to structural diversification. Thus, the stage has been set for the development of non-peptide activators of ClpP that can be used as antibacterial agents.
MIT Department
Massachusetts Institute of Technology. Department of Biology
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DOI of Published Version
https://doi.org/10.1002/cbic.201402358
