Engineered Living Materials for the Delivery of Engineered Probiotics and Therapeutics

用于输送工程益生菌和治疗药物的工程活性材料

• 批准号: 10644157
• 负责人: Taylor H Ware
• 金额: $ 78.84万
• 依托单位: TEXAS ENGINEERING EXPERIMENT STATION
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10644157
• 关键词: 3D Print; Acute; Adherence; Affect; Antibiotic Therapy; Antibiotics; Antibodies; Bacteria; Bacterial Infections; Binding; Biocompatible Materials; Biological; Biological Products; Bladder; Catabolism; Catheters; Cell Proliferation; Cells; Choline; Chronic; Clinical; Data; Devices; Disease Progression; Ecosystem; Engineered Probiotics; Engineering; Epithelial Cells; Escherichia coli; Focal Infection; Goals; Hydrogels; Immune response; In Vitro; Infection; Lead; Malignant Neoplasms; Medical Device; Metabolic; Meteor; Microbial Biofilms; Mus; Nutrient; Nutritional; Organelles; Organism; Outcome; Pathogenicity; Patients; Performance; Pharmaceutical Preparations; Physiologic pulse; Probiotics; Propylene Glycols; Publishing; Recurrence; Resistance; Resources; Source; System; Technology; Testing; Therapeutic; Urinary tract; Urinary tract infection; Urine; Urology; Uropathogen; Uropathogenic E. coli; Urothelium; Woman; Work; base; capsule; controlled release; design; drug resistant pathogen; dysbiosis; fitness; innovation; interdisciplinary approach; intravesical; learning materials; microbiome; microbiome alteration; mouse model; multidisciplinary; multimodality; nanodevice; nanoparticle; new technology; pathogen; probiotic therapy; residence; side effect; small molecule; standard care; synthetic biology; treatment strategy; urinary bladder epithelium

Project Summary Localized infections are often treated with systemic antibiotics, which leads to undesired side effects for the patient and contributes to the increase in antibiotic-resistant pathogens. This work will result in an innovative platform technology, multifunctional engineered living materials and organelles (ELMOs), that alters the metabolic niche occupied by pathogenic organisms and delivers therapeutics. These ELMOs consist of synthetic 1) probiotics engineered with catabolically-active bacterial microcompartments (BMCs) and embedded in hydrogels, 2) standalone catabolically-active BMCs embedded in hydrogels, and 3) BMC-derived shells as therapeutic nanodevices that are released by embedded cellular proliferation. Using this technology, we will build multifunctional intravesical delivery systems that float in the bladder and enable sustained performance to treat urinary tract infections. The proposed interdisciplinary approach leverages advances in synthetic biology and biomaterials and will lead to new technologies designed to treat a wide range of infections, including medical device-associated infections and cancers, where the metabolite availability and dysbiosis contribute to disease progression. Published and preliminary data demonstrate the feasibility of creating engineered living materials comprised of synthetic materials and probiotics and using these materials for controlled release. Published and preliminary data demonstrate that BMCs can be embedded within organisms or isolated to be used as catabolically-active or multivalent binding nanoparticles. Ultimately this work will enable new medical devices that treat infections, beginning with urinary tract infections (UTI), using a multimodal approach that acts against pathogens by modulating the local ecosystem. To realize this goal, three specific aims are proposed: 1) Design intravesical therapeutic and organism delivery systems, 2) Engineer BMCs into non-uropathogenic bacteria and into hydrogels to compete with pathogens, and 3) Determine the effect of ELMOs containing BMC-engineered organisms, catabolically-active BMCs, and therapeutic nanodevices on uropathogen clearance in a mouse model of UTI. The assembled team is well qualified to answer these questions based on multidisciplinary expertise in engineered living materials (Ware), bacterial microcompartments (Kerfeld), UTI (Subash), and clinical urology (Zimmern).

项目概要 局部感染通常采用全身抗生素治疗，这会给患者带来不良副作用 患者，并导致抗生素耐药病原体的增加。这项工作将带来创新 平台技术、多功能工程活性材料和细胞器（ELMO），改变了 病原生物占据的代谢生态位并提供治疗。这些 ELMO 由合成材料组成 1) 益生菌采用具有分解代谢活性的细菌微区室 (BMC) 设计并嵌入 水凝胶，2）嵌入水凝胶中的独立分解代谢活性 BMC，以及 3）BMC 衍生的壳 通过嵌入式细胞增殖释放的治疗性纳米装置。利用这项技术，我们将构建 多功能膀胱内输送系统漂浮在膀胱中并能够持续发挥治疗效果 尿路感染。拟议的跨学科方法利用了合成生物学的进步和 生物材料，并将带来旨在治疗多种感染的新技术，包括医疗感染 与设备相关的感染和癌症，其中代谢物的可用性和生态失调会导致疾病 进展。已发布的初步数据证明了制造工程生活材料的可行性 由合成材料和益生菌组成，并使用这些材料进行控制释放。已发表和 初步数据表明，BMC 可以嵌入生物体内或分离用作 分解代谢活性或多价结合纳米颗粒。最终这项工作将使新的医疗设备成为可能 治疗感染，从尿路感染 (UTI) 开始，采用多模式方法对抗 通过调节当地生态系统来消灭病原体。为了实现这一目标，提出了三个具体目标： 1）设计 膀胱内治疗和生物体递送系统，2) 将 BMC 改造为非尿路致病细菌和 进入水凝胶中与病原体竞争，3) 确定含有 BMC 工程的 ELMO 的效果 生物体、分解代谢活性 BMC 和治疗性纳米装置对小鼠尿路病原体清除的影响 尿路感染模型。组建的团队完全有资格基于多学科来回答这些问题 工程活性材料 (Ware)、细菌微区室 (Kerfeld)、UTI (Subash) 和 临床泌尿外科（Zimmern）。