Examination of a Structural Model of Peptidomimicry by Cyclic Acyldepsipeptide Antibiotics in Their Interaction with the ClpP Peptidase

• Main Authors: Carney, Daniel W. (Author), Scruse, Anthony C. (Author), Sello, Jason K. (Author), Schmitz, Karl Robert (Contributor), Sauer, Robert T. (Contributor)
• Other Authors: Massachusetts Institute of Technology. Department of Biology (Contributor)
• Format: Article
• Language: English
• Published: Wiley Blackwell, 2017-01-10T21:24:37Z.
• Subjects: Article
• Online Access: Get fulltext

 The cyclic acyldepsipeptide (ADEP) antibiotics act by binding the ClpP peptidase and dysregulating its activity. Their exocyclic N-acylphenylalanine is thought to structurally mimic the ClpP-binding, (I/L)GF tripeptide loop of the peptidase's accessory ATPases. We found that ADEP analogues with exocyclic N-acyl tripeptides or dipeptides resembling the (I/L)GF motif were weak ClpP activators and had no bioactivity. In contrast, ADEP analogues possessing difluorophenylalanine N-capped with methyl-branched acyl groups-like the side chains of residues in the (I/L)GF motifs-were superior to the parent ADEP with respect to both ClpP activation and bioactivity. We contend that the ADEP's N-acylphenylalanine moiety is not simply a stand-in for the ATPases' (I/L)GF motif; it likely has physicochemical properties that are better suited for ClpP binding. Further, our finding that the methyl-branching on the acyl group of the ADEPs improves activity opens new avenues for optimization.