Restriction of the Conformational Dynamics of the Cyclic Acyldepsipeptide Antibiotics Improves Their Antibacterial Activity
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Author(s)
Carney, Daniel W.
Schmitz, Karl R.
Truong, Jonathan V.
Sello, Jason K.
Sauer, Robert T
Date Issued
February 2014
Journal
Journal of the American Chemical Society
Publisher
American Chemical Society (ACS)
Citation
Carney, Daniel W., Karl R. Schmitz, Jonathan V. Truong, Robert T. Sauer, and Jason K. Sello. “Restriction of the Conformational Dynamics of the Cyclic Acyldepsipeptide Antibiotics Improves Their Antibacterial Activity.” Journal of the American Chemical Society 136, no. 5 (February 5, 2014): 1922–1929. © 2014 American Chemical Society.
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Final published version
Abstract
The cyclic acyldepsipeptide (ADEP) antibiotics are a new class of antibacterial agents that kill bacteria via a mechanism that is distinct from all clinically used drugs. These molecules bind and dysregulate the activity of the ClpP peptidase. The potential of these antibiotics as antibacterial drugs has been enhanced by the elimination of pharmacological liabilities through medicinal chemistry efforts. Here, we demonstrate that the ADEP conformation observed in the ADEP–ClpP crystal structure is fortified by transannular hydrogen bonding and can be further stabilized by judicious replacement of constituent amino acids within the peptidolactone core structure with more conformationally constrained counterparts. Evidence supporting constraint of the molecule into the bioactive conformer was obtained by measurements of deuterium-exchange kinetics of hydrogens that were proposed to be engaged in transannular hydrogen bonds. We show that the rigidified ADEP analogs bind and activate ClpP at lower concentrations in vitro. Remarkably, these compounds have up to 1200-fold enhanced antibacterial activity when compared to those with the peptidolactone core structure common to two ADEP natural products. This study compellingly demonstrates how rational modulation of conformational dynamics may be used to improve the bioactivities of natural products.
MIT Department
Massachusetts Institute of Technology. Department of Biology
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DOI of Published Version
https://doi.org/10.1021/ja410385c
