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

Boles, Jessica E., Bennett, C., Baker, J., Hilton, Kira L.F., Kotak, H. A., Clark, Ewan R., Long, Y, White, Lisa J., Lai, H. Y., Hind, C. K., and others. (2022) Establishing the selective phospholipid membrane coordination, permeation and lysis properties for a series of ‘druggable’ supramolecular self-associating antimicrobial amphiphiles. Chemical Science, (33). pp. 9761-9773. ISSN 2041-6520. (doi:10.1039/D2SC02630A) (KAR id:96217)

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Official URL: https://doi.org/10.1039/D2SC02630A

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.

Item Type:	Article
DOI/Identification number:	10.1039/D2SC02630A
Projects:	23125
Subjects:	Q Science
Divisions:	Divisions > Division of Natural Sciences > Biosciences Divisions > Division of Natural Sciences > Chemistry and Forensics
Funders:	UK Research and Innovation (https://ror.org/001aqnf71)
Depositing User:	Jennifer Hiscock
Date Deposited:	15 Aug 2022 20:02 UTC
Last Modified:	05 Nov 2024 13:00 UTC
Resource URI:	https://kar.kent.ac.uk/id/eprint/96217 (The current URI for this page, for reference purposes)

University of Kent Author Information

Clark, Ewan R..

Creator's ORCID:	https://orcid.org/0000-0001-7287-2631
CReDIT Contributor Roles:

Garrett, Michelle D..

Creator's ORCID:	https://orcid.org/0000-0002-3939-1673
CReDIT Contributor Roles:

Ortega-Roldan, Jose L..

Creator's ORCID:	https://orcid.org/0000-0002-6316-4390
CReDIT Contributor Roles:

Hiscock, Jennifer R..

Creator's ORCID:	https://orcid.org/0000-0002-1406-8802
CReDIT Contributor Roles:

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