Abstract

Deaths due to antimicrobial-resistant bacteria have surpassed those caused by HIV/AIDS and malaria. Antimicrobial peptides (AMPs) are a promising solution, although their delivery has challenges including poor proteolytic stability and the need for repeated high, localised dosages, traditionally restricting them to topical applications. We explore the use of biocompatible phospholipid bilayers as a platform from which to deliver the antimicrobial peptide GL13K with spaciotemporal control.
In this thesis, the initial focus pertains to the design of a photocleavable GL13K nanoplatform, anchoring peptide to the liposomal surface, as each constituent component had to be considered and many synthesized. GL13K was synthesized with both an o-nitrobenzyl photolabile group and an azide moiety selectively added to the central lysine residue. The nanoplatform is designed such that the bilayer will have an exposed alkyne group. This enables the peptide to be tethered to the phospholipid bilayer using a copper(I)-catalyzed azide-alkyne cycloaddition click reaction, post liposome fabrication. Once the platform was designed, synthesized, and the liposomal vehicles shown to be stable, successful tethering of the peptide was analysed and the GL13K able to adopt the bactericidal β-strand conformation, but not β-sheets when tethered to the liposomal surface. The nanoplatform was shown to have the capability of delivering bactericidal dosages of the AMP justifying future development towards an application in treating chronic wounds infected by persistent biofilm-forming bacteria.