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Elucidating membrane disruption mechanisms of peptide antibiotics

Hammond, Katharine Alexandra; (2020) Elucidating membrane disruption mechanisms of peptide antibiotics. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

Antimicrobial peptides and proteins hold promise as a next generation of antibiotics. Whilst conventional antibiotics must cross the microbial membrane to target intracellular processes, many of these agents act by disrupting microbial lipid bilayers. This alternative mode of action attacks a conserved structural component of the cell and offers a promising alternative for treating infections caused by multi-resistant pathogens. To facilitate the translational development of antimicrobial peptides, it is beneficial to develop a fundamental understanding of their behaviour. However, resolving the interactions between antimicrobial peptides and lipid bilayers is challenging. Disruption to the lipid packing occurs at the nanoscale, is often dynamic and adapts under different environment conditions. Consequently, the rules linking peptide sequence to mechanisms of membrane disruption and biological activity remain largely unknown. The work presented here directly addresses this challenge. AFM imaging of model membrane systems is used to visualise disruption mechanisms with high temporal and spatial resolution. The findings are then compared to biological assays, and reveal new sequence-function relationships. Starting with a simplified α-helical template, we demonstrate that both the mode of lipid disruption and the biological selectivity of a sequence can be controlled at the single amino acid level. Next, we demonstrate that incorporating motifs from membrane-active but non-lytic peptide sequences into an α-helical design can confer auxiliary lipid interactions. Moving on from single α-helices, we provide the first evidence of membrane disruption by multi-helix bacteriocins, resolving a hitherto unknown multimodal mechanism. In addition we resolve the membrane interactions of supramolecular peptide structures, confirming that self-assembly can offer mechanistic advantage. Finally, preliminary data is presented that improves on the chemical and structural specificity of AFM, and therefore the insights into peptide-lipid interactions that it can provide.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Elucidating membrane disruption mechanisms of peptide antibiotics
Event: UCL (University College London)
Open access status: An open access version is available from UCL Discovery
Language: English
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > UCL BEAMS
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences
URI: https://discovery.ucl.ac.uk/id/eprint/10118549
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