Year

2015

Degree Name

Doctor of Philosophy

Department

School of Chemistry

Abstract

Antimicrobial photodynamic therapy (aPDT) uses photosensitiser (PS) molecules in combination with visible light to generate reactive oxygen species (ROS; e.g. 1O2 and •OH) that kill bacteria. The approach is highly suited to skin and other body surface infections, where photosensitisers and light can easily be applied directly to infection sites. As examples, the phenothiazinium PS methylene blue (MB) has been used in aPDT for the sterilisation of blood products, and aPDT with a related compound toluidine blue O (TBO) has been used for oral disinfection of dental cavities and for treating periodontitis.

It has been shown that membrane efflux pumps can limit bacterial cell killing during aPDT with MB, probably by lowering the levels of intracellular ROS produced. This observation suggests that combination approaches, where MB is used alongside small molecule efflux pump inhibitors (EPIs), might potentiate the aPDT effects of MB, allowing its use to be extended to multi-drug resistant (MDR) skin and soft-tissue infections, such as those mediated by methicillin-resistant Staphylococcus aureus (MRSA). Studies have confirmed that combinations of EPIs with MB do indeed show increased aPDT potency relative to MB.

This thesis explored a novel approach where MB was covalently linked to EPIs to create MB-EPI hybrid molecules. The rationale for the approach (Chapter 1) was based on prior studies showing that conjugation of the weak antibacterial berberine to the MDR inhibitor INF55 produced berberine-INF55 hybrids that show increased potency over berberine alone and berberine/INF55 combinations. The similarities between berberine and MB (both planar, aromatic, hydrophobic cations) suggested a similar MB-EPI approach might be successfully adapted for use in aPDT.

FoR codes (2008)

030503 Organic Chemical Synthesis, 039903 Industrial Chemistry, 030499 Medicinal and Biomolecular Chemistry not elsewhere classified, 060802 Animal Cell and Molecular Biology

Share

COinS
 

Unless otherwise indicated, the views expressed in this thesis are those of the author and do not necessarily represent the views of the University of Wollongong.