Antimicrobial sonodynamic therapy

• Main Author: Costley, David John Frederick
• Published: Ulster University 2016
• Subjects: 615.8
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.725338

Antibiotic resistance is an ever increasing threat to global health which is worsened by the lack of viable alternatives to antibiotics. Photodynamic Therapy (PDT) involves the application of light, a sensitiser and molecular oxygen to generate cytotoxic radicals at a specific target and can be used in the treatment of both cancers and bacterial infections. The main limitation of PDT is the lack of penetration of light through tissue restricting PDT to superficial cancers and infections. Sonodynamic Therapy (SDT) is an emerging technique used in the treatment of cancer and involves the targeted generation of cytotoxic radicals through the application of ultrasound in the presence of a sensitiser and molecular oxygen. The advantage of using ultrasound is the ability to target deeper seated infections as it can penetrate further through tissue. Recent studies have indicated that SDT has the potential to be used in the treatment of bacterial infections. In this thesis, antimicrobial SDT will be investigated as a potential treatment for bacterial infections. Chapter 2 includes the methods and materials used in each of the three chapters. The first results chapter (Chapter 3) investigates a range of different sensitisers for their potential use in antimicrobial SDT and establishes ultrasound parameters to optimise treatment in Gram-positive Staphylococcus aureus and Gram-negative Pseudomonas aeruginosa. The antimicrobial SDT efficacy of the sensitisers were compared with their physiochemical properties to determine if any structure-activity relationship was evident. The results generated in this chapter demonstrated that the Gram-negative P. aeruginosa was less susceptible to the treatment than the Gram-positive 5. aureus. Of the sensitisers that were examined, Rose Bengal and Protoporphyrin IX were the best performers. While no unambiguous relationship was established between the structure of the sensitisers and their antimicrobial efficacy, there was a slight trend between the LogD of the sensitisers and their antimicrobial efficacy. These findings indicated that uptake of the sensitisers was a more important factor than the degree of cytotoxic radical generation. The second results chapter (Chapter 4) expanded upon the findings from Chapter 3 and involved the synthesis of a Rose Bengal-peptide conjugate that aimed to increase the efficacy of SDT in P. aeruginosa. It was observed that the conjugation of the peptide increased the uptake of Rose Bengal in P. aeruginosa and S. aureus which also coincided with a significant increase in the effectiveness of the SDT treatment towards P. aeruginosa. A pilot in vivo study also indicated that antimicrobial SDT may be an effective treatment for localised bacterial infections. The third results chapter (Chapter 5) investigated the potential of a combined antimicrobial near infrared (NIR) PDT / SDT treatment using newly synthesised iodinated cyanine dye- based sensitisers. Minimal reductions in bacterial viability were observed when using SDT with larger reductions observed using NIR PDT with the exception of P. aeruginosa which showed little to no response to PDT treatment. Simultaneous treatment of S. aureus with PDT and SDT proved very effective in clearing the bacterial population, however P. aeruginosa remained unresponsive to the combined treatment. Chapter 6 summarises the conclusions and provides an outlook for future work.