Switchable foldamer ion channels with antibacterial activity.

Anna D Peters,George F S Whitehead,Stefan Borsley,Jonathan Clayden,Flavio Della Sala,Dominic F Cairns-Gibson,Simon J Webb,Marios Leonidou,Eriko Takano,Scott L Cockroft,John Burthem,Iñigo J Vitórica-Yrezábal

doi:10.1039/d0sc02393k

Abstract

Synthetic ion channels may have applications in treating channelopathies and as new classes of antibiotics, particularly if ion flow through the channels can be controlled. Here we describe triazole-capped octameric α-aminoisobutyric acid (Aib) foldamers that "switch on" ion channel activity in phospholipid bilayers upon copper(ii) chloride addition; activity is "switched off" upon copper(ii) extraction. X-ray crystallography showed that CuCl2 complexation gave chloro-bridged foldamer dimers, with hydrogen bonds between dimers producing channels within the crystal structure. These interactions suggest a pathway for foldamer self-assembly into membrane ion channels. The copper(ii)-foldamer complexes showed antibacterial activity against B. megaterium strain DSM319 that was similar to the peptaibol antibiotic alamethicin, but with 90% lower hemolytic activity.

Highlights

Natural ion channels carry out key functions in cellular membranes, including chemical and electrical signal transduction, control of cell volume, and maintenance of internal ion concentrations.1 Ion channel function is necessarily tightly regulated, as unregulated function can result in a disease state
Synthetic ionophores could potentially alleviate the symptoms of channelopathies5,6 or provide new antibiotic classes able to overcome the growing aDepartment of Chemistry, University of Manchester, Oxford Road, Manchester M13 9PL, UK
We have shown that the structurally related N,N-bis(quinolin-2ylmethyl)-N-((50-carboxypyridyl)methyl)amine (BQPA) motif at the N-terminus of foldamers complexes tightly to Cu(II) and Zn(II).19b,23 Much like related N,N,N-tris(pyridin-2-ylmethyl) amine (TPA) complexes,24 the BPTA group should adopt a trigonal pyramidal geometry around the metal ion with at least one potential coordination site for external ligands

Summary

Introduction

Natural ion channels carry out key functions in cellular membranes, including chemical and electrical signal transduction, control of cell volume, and maintenance of internal ion concentrations.1 Ion channel function is necessarily tightly regulated, as unregulated function can result in a disease state. Tetrameric Aib foldamer 7 was produced from 5 using a similar procedure, providing the control compound with a much shorter membrane-active unit (the “stave”).

Results

Conclusion