Webley, Catherine Ruth; (2024) Pore-Forming Behaviour of Nisin and Nisin-Mimetics in Model Membranes. Doctoral thesis (Ph.D), UCL (University College London).

Text Webley_19100571_PhD_Thesis.pdf - Accepted Version Access restricted to UCL open access staff until 1 May 2025. Download (57MB)

Abstract

Antimicrobial resistance is a global health threat that requires innovative solutions. The antimicrobial peptide nisin is promising due to its non-toxicity and low resistance rates despite widespread use as a food preservative. However, nisin has poor oral bioavailability, solubility, and stability. Nisin has a dual mode of action. This involves binding and sequestration of Gram-positive bacterial cell wall precursor lipid II. Additionally, nisin forms nanopores that puncture the bacterial cell membrane causing efflux of cell nutrients and collapse of the cell ionic potential. The dominant mode of action and precise nanopore architecture are currently unknown. In this work, biophysical techniques were applied to unresolved questions concerning nisin’s pore-forming activity. Single-channel current recordings were used to determine nisin’s pore conductance and pore size. Measurements on model membranes with variable anionic content revealed how the lipid environment influences peptide-mediated poration. Larger pores of ∼ 2 nm diameter were observed in membranes with higher anionic content. This may reflect nisin activity in biological systems. Native nisin was compared with semi-synthetic structural analogues to probe linearisation of up to three of nisin’s five thioether bridged lanthionine rings. Antimicrobial activity of the bacterial cell membrane-targeting nisin AB rings conjugated onto a linear pore-forming peptide was investigated alongside the role of nisin’s C ring (the hinge region). Findings suggest retention of pore-forming activity following linearisation of nisin’s C, D and E rings with a reduction in pore diameter. Insight gained may inform design of nisin-like antibiotics with improved drug properties and unique modes of action.

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