Establishing the selective phospholipid membrane coordination,permeation and lysis properties for a series of ‘druggable’ supramolecular self-associating antimicrobial amphiphiles |
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| Authors: | Jessica E. Boles Charlotte Bennett Jennifer Baker Kira L. F. Hilton Hiral A. Kotak Ewan R. Clark Yifan Long Lisa J. White Hin Yuk Lai Charlotte K. Hind J. Mark Sutton Michelle D. Garrett Anne Cheasty Jose L. Ortega-Roldan Mark Charles Cally J. E. Haynes Jennifer R. Hiscock |
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| Affiliation: | School of Chemistry and Forensics, University of Kent, Canterbury CT2 7NH UK.; School of Biosciences, University of Kent, Canterbury CT2 7NJ UK ; Cancer Research Horizons, 2 Redman Place, London E20 1JQ UK.; Chemistry Department, UCL, 20 Gordon Street, London WC1H 0AJ UK.; Research and Evaluation, Porton Down, UKHSA, Porton Down, Salisbury SP4 0JG UK ; Exscientia, The Schrödinger Building, Heatley Road, Oxford Science Park, Oxford OX4 4GE UK |
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| 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.A combination of computational and synthetic phospholipid vesicle/nanodisc assays are used to investigate the mode of action for a class of antimicrobial agents, while a range of DMPK studies establish agent druggability. |
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