Consequences of Depsipeptide Substitution on the ClpP Activation Activity of Antibacterial Acyldepsipeptides

Yangxiong Li, Nathan P. Lavey, Jesse A. Coker, Jessica E. Knobbe, Dat C. Truong, Hongtao Yu, Yu Shan Lin, Susan L. Nimmo, Adam S. Duerfeldt

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

The acyldepsipeptide (ADEP) antibiotics operate through a clinically unexploited mechanism of action and thus have attracted attention from several antibacterial development groups. The ADEP scaffold is synthetically tractable, and deep-seated modifications have produced extremely potent antibacterial leads against Gram-positive pathogens. Although newly identified ADEP analogs demonstrate remarkable antibacterial activity against bacterial isolates and in mouse models of bacterial infections, stability issues pertaining to the depsipeptide core remain. To date, no study has been reported on the natural ADEP scaffold that evaluates the sole importance of the macrocyclic linkage on target engagement, molecular conformation, and bioactivity. To address this gap in ADEP structure-activity relationships, we synthesized three ADEP analogs that only differ in the linkage motif (i.e., ester, amide, and N-methyl amide) and provide a side-by-side comparison of conformational behavior and biological activity. We demonstrate that while replacement of the naturally occurring ester linkage with a secondary amide maintains in vitro biochemical activity, this simple substitution results in a significant drop in whole-cell activity. This study provides direct evidence that ester to amide linkage substitution is unlikely to provide a reasonable solution for ADEP instability.

Original languageEnglish (US)
Pages (from-to)1171-1176
Number of pages6
JournalACS Medicinal Chemistry Letters
Volume8
Issue number11
DOIs
StatePublished - Nov 9 2017
Externally publishedYes

Bibliographical note

Funding Information:
This work was partially funded by the Oklahoma Center for the Advancement of Science and Technology (OCAST, HR15-161) and University of Oklahoma start-up funds. Research reported in this publication was also supported by an Institutional Development Award (IDeA) from the National Institute of General Medical Sciences of the National Institutes of Health (P20GM103640).

Keywords

  • Caseinolytic protease P
  • acyldepsipeptide
  • antibacterial
  • depsipeptide substitution

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