Engineered Living Materials for the Delivery of Engineered Probiotics and Therapeutics

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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).