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

Research output: Contribution to journalArticle

  • Catherine Adam
  • Anna D. Peters
  • M. Giovanna Lizio
  • George F. Whitehead
  • Vincent Diemer
  • James Cooper
  • Scott Cockroft
  • Jonathan Clayden
  • Simon J. Webb

Related Edinburgh Organisations

Original languageEnglish
JournalChemistry - A European Journal
Early online date6 Dec 2017
DOIs
StateE-pub ahead of print - 6 Dec 2017

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 2.91 nm 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.

ID: 48357336