Development of New Ultrasound Sensitive Antimicrobial Therapeutics for Antibiofilm Therapy

用于抗菌膜治疗的新型超声敏感抗菌疗法的开发

• 批准号: 2594356
• 金额: --
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2594356
• 关键词: Development; New; Ultrasound; Sensitive; Antimicrobial

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.

抗生素耐药性是一种新出现的全球健康流行病，导致全球超过75万人死亡，仅在美国就造成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是生活在多物种微生物群落中;与传统抗菌剂靶向的自由漂浮的寄生菌不同。治愈性治疗极大地受限于带电抗菌剂的受限渗透和超出胞外多糖基质的宿主免疫防御。因此，存在对靶向生物膜群落的安全和有效的治疗范例的关键未满足的需求，以克服常规疗法的不足。Sonobactericide是一种新兴的非侵入性治疗平台，具有既定的安全性，耐受性和满足这些需求的能力，而不会增强多药耐药性。通过超声波，抗菌剂的受控局部释放允许选择性积聚和外渗到目标细菌群落。通过整合高压超声波进行精确治疗，sonobactericide具有瞬时破坏胞外多糖基质的潜力，以改变生物膜粘附和二次杀菌效果，同时增加治疗剂向细菌群落的递送。总之，存在真正选择性、微创、高有效载荷递送和治疗生物膜相关感染的可能性。具体而言，刺激响应材料必须被设计用于持续和靶向药物释放以实现杀菌效果，同时利用高强度聚焦超声本身改变生物膜粘附并协同增强治疗敏感性的能力。此外，用靶向分子装饰纳米载体表面的可能性促进了通过生物屏障，并且将使得能够具有高的空间和时间特异性，同时最小限度地释放封装的药物到其他器官。基于充气纳米囊泡在改变生物膜粘附中的机制，我们假设负载的新型抗微生物化合物的增强递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杀菌剂平台，以同时绕过胞外多糖基质并向多微生物生物膜提供有效的协同剂介导的杀菌治疗，同时机械破坏临床感染中的生物膜。总的来说，我们设想我们的工作产生一种新的杀声细菌纳米液滴平台，可以有意义地影响生物膜的功效，同时改变未来的药剂设计策略。在这样做的过程中，该项目将声波杀菌剂作为一种非侵入性平台，在没有抗生素耐药性风险的情况下治疗生物膜。我们期待使用我们的抗菌平台，以一种新颖、有效的方式实现这些功能，作为第一个考虑到机制的合理设计的抗生物膜平台。如果成功，我们希望将这项工作转化到非人类灵长类动物中，目标是实现临床转化。这项创新具有广泛的影响力，在广泛的疾病状态中具有潜在的临床意义。本项目属于EPSRC临床技术研究领域的福尔斯。该小组的临床合作者是纳菲尔德骨科医院的骨感染科、皇家自由医院和约翰拉德克利夫医院的泌尿科以及南安普顿大学医院。行业合作伙伴将包括GSK、Norbrook Laboratories、Oxford Nano Imaging、Smith and Nephew、Boston Scientific和Storz。我们的政策合作者将是英国公共卫生，UKCEH和行为洞察团队。