title: Examination of a Structural Model of Peptidomimicry by Cyclic Acyldepsipeptide Antibiotics in Their Interaction with the ClpP Peptidase.
abstract: 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.
authors.affiliation: Department of Chemistry, Brown University, 324 Brook Street, Providence, RI 02912 (USA).
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Carney
authors.affiliation: Department of Biology, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139 (USA).
authors.forename: Karl R
authors.initials: KR
authors.lastname: Schmitz
authors.affiliation: Department of Chemistry, Brown University, 324 Brook Street, Providence, RI 02912 (USA).|Department of Chemistry, Morehouse College, 830 Westview Drive SW, Atlanta, GA 30312 (USA).
authors.forename: Anthony C
authors.initials: AC
authors.lastname: Scruse
authors.affiliation: Department of Biology, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139 (USA).
authors.forename: Robert T
authors.initials: RT
authors.lastname: Sauer
authors.affiliation: Department of Chemistry, Brown University, 324 Brook Street, Providence, RI 02912 (USA).
authors.forename: Jason K
authors.initials: JK
authors.lastname: Sello
keywords: ClpP; acyldepsipeptides; antibacterials; peptidomimicry; proteolysis