A Study of The Effect of Membrane Targeting Antimicrobial Compounds on Ionic Transport Across Lipid Bilayer Membranes

The novel synthetic cationic peptide melimine is a chimera of two natural peptides, melittin and protamine. This peptide has a broad spectrum of antibacterial activity against both gram-positive and gram-negative bacteria while having no toxicity in mammalian cells. Melimine was initially synthesised as a coating for contact lenses as a way of reducing keratitis, inflammation of the cornea. However, its antibacterial effects also have further potential use as an antimicrobial coating for other biomaterial surfaces. This peptide has been studied along with four peptide derivatives to determine the effects that peptide hydrophobicity, charge and size have on the peptides’ antibacterial properties through studying their peptide-membrane interactions. Melimine has previously been shown to reduce the integrity of membranes, observed through the leakage of dye from bacterial membranes. The membrane-peptide interactions were compared using advanced lipid membrane biophysical techniques, including in-silico structural modelling, fluorescent membrane dipole measures, differential scanning calorimetry, neutron reflectometry, dynamic light scattering and electrical impedance spectroscopy and Arrhenius measures of their interactions with tethered bilayer lipid membranes (tBLMs). Through analysing the results obtained from these biophysical techniques, the peptide-membrane interactions of melimine and its derivatives were compared against known modes lipid membrane interactions of antimicrobial compounds. These interactions included the barrel-stave model, carpet model, interdigitated toroidal pore model, critical packing parameter model and other surfactant-like properties. The five peptides showed minimal peptide-membrane interactions and an inability to span a lipid bilayer, leading to a postulation that these five peptides do not conform to having one of these aforementioned modes of action in killing bacteria. The limited peptide-membrane interactions of the five cationic peptides contrast with their known antibacterial activity against bacteria. This suggests that melimine and its derivatives may interact with other components of bacterial cell membranes; this could include extracellular components, such as porin channels. This research highlights that the assumption that cationic peptides adhere to established membrane disruption models for their antimicrobial activity requires reconsideration. This study emphasises the need for an alternative model of the antibacterial effects of cationic peptides such as melimine and its derivatives.

Author dc:creator

• Berry, Thomas

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• The author owns the copyright in this thesis including all reproduction and reuse rights for the work. The work may not be altered without the permission of the copyright owner. Attribution is essential when quoting or paraphrasing from this thesis.
• au.edu.uts.lib/ppc
• info:eu-repo/semantics/openAccess

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en_US

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http://hdl.handle.net/10453/150770

OAI identifier oai:identifier

oai:opus.lib.uts.edu.au:10453/150770