Development of new ultrasound sensitive antimicrobial therapeutics for antibiofilm therapy

Thesis

Chronic and nosocomial infections present a major clinical challenge, exacerbated by the global rise in antibiotic-resistant bacteria and an aging comorbid population. In 80% of these cases, the formation of protective bacterial biofilms severely undermines the efficacy of conventional antibiotics and host immune responses, as bacteria become shielded within a protective extracellular matrix.

Despite the urgency, alternative therapies have largely failed to overcome biofilm defenses, frequently failing to eradicate dormant persister cells and/or disrupt the biofilm matrix, enabling bacteria to recolonize and trigger infection recurrence, often with heightened drug resistance.

Aligned with the WHO Global Action Plan on AMR, this thesis investigates the development of a novel ultrasound-sensitive antimicrobial platform designed to enhance antibiofilm efficacy through targeted drug delivery and mechanical disruption of biofilm structures. The research focuses on the design, synthesis, and physicochemical and microbiological evaluation of a range of different antimicrobialloaded ultrasound-responsive agents (AURAs), or nanodroplets (NDs). Upon ultrasound activation, these nanodroplets undergo acoustic droplet vaporization (ADV) in a process that physically disrupts the biofilm matrix, enabling the penetration and localized delivery of loaded antimicrobials

In vitro studies using a clinical ultrasound probe demonstrated that AURAs enhanced antimicrobial delivery into the cytoplasm of biofilm-embedded bacteria by 5.5-fold and enhanced efficacy by 44.4-fold. These results were accompanied by superior biofilm dispersal, matrix disruption, and eradication of dormant cells. Preclinical studies using clinically relevant multispecies artificial biofilm models confirmed that AURAs significantly reduced therapeutic doses while improving bacterial clearance. Pilot in vivo studies on a chronic wound model using a new AURA hyaluronic acid gel strategy demonstrated a 2.69-fold reduction in bacterial bioluminescence 4.5 hours post-treatment compared to drug alone.

This thesis advances ultrasound-sensitive antimicrobial therapeutics as a promising strategy for biofilm-associated infections, offering a foundation for the development of targeted therapies that address current treatment limitations and contribute to combatting the risk of AMR.

Authors: Choi, V

• DOI: 10.5287/ora-zbne4e1en
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Subjects: Biomedical engineering