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. 2020 Jun 4;11(27):7023-7030.
doi: 10.1039/d0sc02393k. eCollection 2020 Jul 21.

Switchable foldamer ion channels with antibacterial activity

Anna D Peters  1   2 , Stefan Borsley  1   3 , Flavio Della Sala  1   2 , Dominic F Cairns-Gibson  3 , Marios Leonidou  1   2 , Jonathan Clayden  4 , George F S Whitehead  1 , Iñigo J Vitórica-Yrezábal  1 , Eriko Takano  1   2 , John Burthem  5   6 , Scott L Cockroft  3 , Simon J Webb  1   2
Affiliations

Switchable foldamer ion channels with antibacterial activity

Anna D Peters et al. Chem Sci. .

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.

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Figures

Fig. 1
Fig. 1. Structure of Aib foldamers 1 and 2.
Scheme 1
Scheme 1. Synthesis of Aib foldamers 1, 2 and 7 and their corresponding copper(ii) chloride complexes.
Fig. 2
Fig. 2. (a and b) X-ray crystal structures of (a) 2, (b) [Cu(ii)[2](μ-Cl)]2Cl2 and (c) [Cu(ii)[2]Cl]·HCO3, with bicarbonate ion indicated (boxed). (d) Channels within the X-ray crystal structure of [Cu(ii)[2](μ-Cl)]2Cl2.
Fig. 3
Fig. 3. (a and b) HPTS assays of (a) MeOH (•), 1 (), Cu(ii)[1]Cl2 () and (b) MeOH (•), 2 () and Cu(ii)[2]Cl2 () (all 10 μM except Cu(ii)[2]Cl2 6 μM) in phospholipid vesicles (760 μM lipid) in the presence of KCl (100 mM). Compounds added at 0 min, base pulse at 1 min, TX-100 added at 7 min allows data normalisation. (c) Switching of ionophoric activity for 1 (10 μM) and 2 (6 μM) in the presence of KCl (100 mM); CuCl2 addition (2 eq.) at 120 s followed by EDTA addition (2.2 eq.) at 180 s. Compounds added at 0 min, base pulse at 1 min, TX-100 added at 7 min allows data normalisation. The corresponding data for the addition of MeOH (20 μL) has been subtracted from these data in (c).
Fig. 4
Fig. 4. Ionophoric activity of Cu(ii)[2]Cl2 (6 μM) determined through HPTS assays in the presence of different salts (all 100 mM): (a) KCl (), NaCl (), LiCl (), RbCl (); (b) KCl (), KI (), K2SO4 (), KBr (), KNO3 (•). Compounds added at 0 min, base pulse at 1 min, TX-100 addition at 7 min allows data normalisation.
Fig. 5
Fig. 5. Lucigenin assays of Cl– transport by MeOH (•), 2 (10 μM, ) and Cu(ii)[2]Cl2 (10 μM, ) with interior NaNO3 (200 mM) and exterior NaCl (2 M). Compounds added at 0 min, NaCl added at 1 min, TX-100 addition at 7 min allows data normalization.
Fig. 6
Fig. 6. Step changes in conductance induced by Cu(ii) complexes of 2 added to cis side of the membrane. Membranes were formed from EYPC lipid/cholesterol (4 : 1, w/w) in MOPS buffer at room temperature (20 mM MOPS, 100 mM NaCl, pH 7.4). Change from 0 pA (grey bars) indicated by green arrows. Green bars mark the approximate level of a single quantized current-step. (a) Green complex ([Cu(ii)[2](μ-Cl)]2Cl2, final concentration 8.3 μM). (b) Blue complex ([Cu(ii)[2]Cl]·HCO3, final concentration 8.3 μM).
Fig. 7
Fig. 7. (a) MIC against B. megaterium strain DSM319. (b) Haemolysis of human erythrocytes caused by alamethicin (•) and 1 (), Cu(ii)[1]Cl2 (), 2 () and Cu(ii)[2]Cl2 ().
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