Development of New Ultrasound Sensitive Antimicrobial Therapeutics for Antibiofilm Therapy

抗生素耐药性是一种新兴的全球健康大流行，导致全球超过75万人死亡，仅在美国就造成了550亿美元的经济负担。事实上，社区和医院环境中的细菌通常被认为生活在多物种微生物群落中；与传统抗菌剂针对的自由漂浮浮游细菌不同。根治疗法在很大程度上受到带电抗菌剂的渗透限制和超出胞外多糖基质的宿主免疫防御的限制。因此，存在针对生物膜社区的安全和有效的治疗范例的迫切需求，以克服传统疗法的不足。声细菌杀菌剂是一种新兴的非侵入性治疗平台，具有公认的安全性、耐受性和能力，可以在不增加多药耐药性的情况下满足这些需求。通过超声波，抗菌剂的局部受控释放允许选择性地积累和外渗到目标细菌群落。通过集成高压超声波进行精确治疗，声波杀菌剂具有瞬时破坏胞外多糖基质以改变生物膜粘附性和二次杀菌效果的潜力，同时增加治疗药物对细菌群落的输送。综上所述，存在着真正选择性、微创、高有效载荷输送和治疗生物被膜相关感染的可能性。具体地说，刺激响应性材料必须设计用于持续和靶向的药物释放，以达到杀菌效果，同时利用高强度聚焦超声本身改变生物膜附着的能力，并协同提高治疗敏感性。此外，用靶向分子修饰纳米载体表面的可能性可以促进生物屏障的通过，并能够在最大限度地将包裹的药物释放到其他器官的情况下具有高度的空间和时间特异性。基于充气纳米囊泡改变生物膜粘连的机制，我们假设，加强负载新型抗菌化合物的输送将协同治疗由耐药生物膜菌株引起的慢性感染。在这里，我们建议开发一种改变范式的高强度声波杀菌剂平台，以同时绕过胞外多糖基质，并为多菌生物膜提供有效的协同制剂介导的杀菌治疗，同时机械地破坏临床感染中的生物膜。总体而言，我们的工作是生产一种新型的声波杀菌剂纳米液滴平台，该平台可以在改变未来的制剂设计策略的同时，对生物膜的效率产生有意义的影响。在这样做的过程中，该项目将声波杀菌剂推向了其作为非侵入性平台治疗生物膜而不存在抗生素耐药性风险的前景。我们预计将使用我们的抗菌平台以一种新颖、有效的方式实现这些能力，作为第一个考虑到机制的合理设计的抗生物被膜平台。如果成功，我们希望将这项工作翻译到非人类灵长类动物，目标是临床翻译。这项创新有可能产生广泛的影响，在广泛的疾病状态下具有潜在的临床意义。该项目属于EPSRC临床技术研究领域。该团队的临床合作者是纳菲尔德整形外科医院的骨感染科，皇家自由医院和约翰·拉德克利夫医院的泌尿外科，以及南安普顿大学医院。行业合作伙伴将包括葛兰素史克、诺布鲁克实验室、牛津纳米成像公司、Smith and Nephew、波士顿科学公司和Storz公司。我们的政策协作者将是英国公共卫生组织、英国卫生与公众服务部和行为洞察团队。

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.