Engineered Living Materials for the Delivery of Engineered Probiotics and Therapeutics

项目摘要 局部感染通常用全身性抗生素治疗，这会导致对 患者，并导致抗药性病原体的增加。这项工作将产生一种创新的 平台技术，多功能工程生物材料和细胞器(ELMOS)，改变了 病原体占据的新陈代谢生态位，提供治疗药物。这些Elmos由合成的 1)利用分解活性细菌微室(BMC)工程的益生菌并嵌入到 水凝胶，2)嵌入水凝胶中的独立的分解活性的BMC，以及3)BMC衍生的壳作为 通过嵌入的细胞增殖释放的治疗性纳米设备。使用这项技术，我们将建立 多功能膀胱内给药系统，漂浮在膀胱内，能够持续发挥治疗作用 尿路感染。拟议的跨学科方法利用合成生物学和 生物材料，并将导致旨在治疗广泛感染的新技术，包括医疗 设备相关性感染和癌症，代谢物可获得性和生物失调导致疾病 进步。已发表的和初步的数据证明了创造工程生物材料的可行性 由合成材料和益生菌组成，并使用这些材料进行控制释放。出版并出版 初步数据表明，骨髓基质细胞可以植入生物体内或分离出来用作 分解活性纳米颗粒或多价结合纳米颗粒。最终，这项工作将使新的医疗设备 从尿路感染(UTI)开始，使用多模式方法治疗感染，以对抗 通过调节当地的生态系统来控制病原体。为了实现这一目标，提出了三个具体目标：1)设计 膀胱内治疗和生物递送系统，2)将骨髓细胞工程成非泌尿系致病细菌和 变成水凝胶与病原体竞争，以及3)确定含有BMC-Engineering的Elmos的效果 生物体、具有分解代谢活性的骨髓细胞和治疗性纳米器件对小鼠尿路病原体清除的影响 UTI模型。集合的团队完全有资格回答这些基于多学科的问题 工程生物材料(Ware)、细菌微隔室(Kerfeld)、UTI(Subash)和 临床泌尿科(齐默恩)。

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).