The Role of Terminal Functionality in the Membrane and Antibacterial Activity of Peptaibol-Mimetic Aib Foldamers

Catherine Adam, Anna D. Peters, M. Giovanna Lizio, George F.S. Whitehead, Vincent Diemer, James A. Cooper, Scott L. Cockroft, Jonathan Clayden*, Simon J. Webb

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)

6 Citations (Scopus)
222 Downloads (Pure)

Abstract

Peptaibols are peptide antibiotics that typically feature an N-terminal acetyl cap, a C-terminal aminoalcohol, and a high proportion of α-aminoisobutyric acid (Aib) residues. To establish how each feature might affect the membrane-activity of peptaibols, biomimetic Aib foldamers with different lengths and terminal groups were synthesised. Vesicle assays showed that long foldamers (eleven Aib residues) with hydrophobic termini had the highest ionophoric activity. C-terminal acids or primary amides inhibited activity, while replacement of an N-terminal acetyl with an azide group made little difference. Crystallography showed that N3Aib11CH2OTIPS folded into a 310 helix 2.91nm long, which is close to the bilayer hydrophobic width. Planar bilayer conductance assays showed discrete ion channels only for N-acetylated foldamers. However long foldamers with hydrophobic termini had the highest antibacterial activity, indicating that ionophoric activity in vesicles was a better indicator of antibacterial activity than the observation of discrete ion channels.

Original languageEnglish
Pages (from-to)2249-2256
Number of pages8
JournalChemistry - A European Journal
Early online date17 Jan 2018
DOIs
Publication statusPublished - 9 Feb 2018

Keywords

  • Antibiotics
  • Biological activity
  • Foldamers
  • Ion channels
  • Peptides

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    Molecular Robotics

    Clayden, J. P.

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    Cite this

    Adam, C., Peters, A. D., Lizio, M. G., Whitehead, G. F. S., Diemer, V., Cooper, J. A., Cockroft, S. L., Clayden, J., & Webb, S. J. (2018). The Role of Terminal Functionality in the Membrane and Antibacterial Activity of Peptaibol-Mimetic Aib Foldamers. Chemistry - A European Journal, 2249-2256. https://doi.org/10.1002/chem.201705299