Issue 33, 2022

Establishing the selective phospholipid membrane coordination, permeation and lysis properties for a series of ‘druggable’ supramolecular self-associating antimicrobial amphiphiles

Abstract

The rise of antimicrobial resistance remains one of the greatest global health threats facing humanity. Furthermore, the development of novel antibiotics has all but ground to a halt due to a collision of intersectional pressures. Herein we determine the antimicrobial efficacy for 14 structurally related supramolecular self-associating amphiphiles against clinically relevant Gram-positive methicillin resistant Staphylococcus aureus and Gram-negative Escherichia coli. We establish the ability of these agents to selectively target phospholipid membranes of differing compositions, through a combination of computational host:guest complex formation simulations, synthetic vesicle lysis, adhesion and membrane fluidity experiments, alongside our novel 1H NMR CPMG nanodisc coordination assays, to verify a potential mode of action for this class of compounds and enable the production of evermore effective next-generation antimicrobial agents. Finally, we select a 7-compound subset, showing two lead compounds to exhibit ‘druggable’ profiles through completion of a variety of in vivo and in vitro DMPK studies.

Graphical abstract: Establishing the selective phospholipid membrane coordination, permeation and lysis properties for a series of ‘druggable’ supramolecular self-associating antimicrobial amphiphiles

Supplementary files

Article information

Article type
Edge Article
Submitted
10 5 2022
Accepted
03 8 2022
First published
10 8 2022
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY license

Chem. Sci., 2022,13, 9761-9773

Establishing the selective phospholipid membrane coordination, permeation and lysis properties for a series of ‘druggable’ supramolecular self-associating antimicrobial amphiphiles

J. E. Boles, C. Bennett, J. Baker, K. L. F. Hilton, H. A. Kotak, E. R. Clark, Y. Long, L. J. White, H. Y. Lai, C. K. Hind, J. M. Sutton, M. D. Garrett, A. Cheasty, J. L. Ortega-Roldan, M. Charles, C. J. E. Haynes and J. R. Hiscock, Chem. Sci., 2022, 13, 9761 DOI: 10.1039/D2SC02630A

This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. You can use material from this article in other publications without requesting further permissions from the RSC, provided that the correct acknowledgement is given.

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