Development of New Ultrasound Sensitive Antimicrobial Therapeutics for Antibiofilm Therapy

Antibiotic resistance is an emerging global health pandemic attributed to over 750,000 deaths globally, causing an economic burden of $55 billion within the United States alone. Indeed, bacteria in community and nosocomial settings are generally recognized to live within multispecies microbial communities; far unlike the free-floating planktonic bacteria targeted with traditional antimicrobial agents. Curative treatment is greatly limited by restricted permeation of charged antimicrobials and host immune defences beyond the exopolysaccharide matrix. As such, there exists a critical unmet need for safe and effective treatment paradigms targeting biofilm communities to overcome shortfalls in conventional therapies.
Sonobactericide is an emerging non-invasive therapeutic platform with established safety, tolerability, and capacity to meet these needs without potentiating multi-drug resistance. Through ultrasound, controlled local release of antimicrobials allow for selective accumulation and extravasation to target bacterial communities. By integrating high-pressure ultrasound for precision treatment, sonobactericide holds potential to transiently disrupt the exopolysaccharide matrix for alteration of biofilm adhesion and secondary bactericidal effect whilst increasing delivery of therapeutic agents to bacterial communities. Taken together, there exists possibility for truly selective, minimally invasive, high payload delivery and treatment of biofilm-related infections.
Specifically, stimuli-responsive materials must be engineered for sustained and targeted drug release for bactericidal effect, whilst capitalizing upon the ability of high intensity focused ultrasound to, itself, alter biofilm adhesion and synergistically enhance therapeutic susceptibility. Moreover, the possibility of decorating the surface of the nanocarrier with targeting molecules promotes passage through biological barriers and would enable with high spatial and temporal specificity with minimal release of encapsulated drug to other organs. Building upon the mechanism of gas-filled nanomeric vesicles in altering biofilm adhesion, we hypothesize that enhanced delivery of loaded novel antimicrobial compounds will synergistically treat chronic infections caused by drug-resistant biofilm strains.
Here, we propose to develop a paradigm-changing high-intensity sonobactericide platform to simultaneously bypass the exopolysaccharide matrix and deliver efficacious, synergistic agent-mediated bactericidal therapy to polymicrobial biofilms whilst mechanically disrupting biofilms in clinical infections.
Overall, we envision our work to yield a novel sonobactericide nanodroplet platform that can meaningfully impact biofilm efficacy alongside altering future agent design strategy moving forward. In doing so, this project advances sonobactericide towards its promising potential as a non-invasive platform to treat biofilms without risk of antibiotic resistance. We anticipate the use of our antimicrobial platform to enable these capabilities in a novel, impactful manner as the first rationally engineered anti-biofilm platform with mechanism in-mind. With success, we hope to translate this work to non-human primates with the goal towards clinical translation. This innovation holds potential to have broad impact, with potential clinical implications across a wide scope of disease states. This project falls within the EPSRC Clinical Technologies research area.
The team's clinical collaborators are The Bone Infection Unit at Nuffield Orthopaedic Hospital, Departments of Urology at Royal Free and John Radcliffe Hospitals and University Hospitals Southampton. Industry collaborators will include GSK, Norbrook Laboratories, Oxford Nano Imaging, Smith and Nephew, Boston Scientific and Storz. Our policy collaborators will be Public Health England, UKCEH and The Behavioural Insights Team.