Microbubbles for the treatment of Staphylococcus aureus biofilms: Tackling Antimicrobial Resistance in New Ways

Bacterial biofilms are organized microbial communities embedded within a protective extracellular matrix. Biofilms, specifically those of Staphylococcus aureus, are notorious for their tendency towards forming on implanted medical devices such as catheters, prostheses, and heart valves. With an ageing population worldwide, the number of implanted devices is on the rise making this a growing issue. Biofilms are responsible for approximately 80% of human infections and their formation is associated with dramatically enhanced resistance to antimicrobials, further complicating their treatment. The proliferation of antimicrobial resistance is another significant issue that further adds to the challenges associated with biofilm infections. The issue of resistance has been exacerbated by a lapse in the discovery of new antibiotics.. At present, there are a limited number of effective therapies available for the treatment of biofilms, and in many cases, the simple removal and replacement of such devices is the only suitable option. Microbubbles are micron-sized surfactant-coated gas bubbles that have been developed as ultrasound contrast agents for use in diagnostic ultrasound imaging. The interactions between ultrasound and microbubbles have been observed to produce a plurality of useful bioeffects, including the outright killing of bacterial cells, and enhanced delivery of therapeutic agents to biofilms. Molecular targeting of bacterial biofilms offers a new method for the detection of bloodstream-based infections. Further, targeting may offer a potential method of improved treatment when combined with drugs or delivery vehicles, such as liposomes. In this thesis, we investigate the specific targeting of microbubbles to S. aureus biofilms via a novel Affimer protein which showed an 8-fold increase in surface adherence compared to a control isotype. We then applied US-mediated destruction of microbubbles as a potential method of treating biofilms. These studies were performed within a bespoke microfluidic platform, specifically designed for these investigations. We then explored the combination of ultrasound and microbubbles for the enhanced delivery of antimicrobial agents against S. aureus biofilms.