Development of Faux-Biotics to combat the spread of hospital-acquired antibiotic-resistant infections

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Project Summary The CDC considers the escalation of antibiotic resistance to be one of the biggest public health concerns of our time. Antibiotic resistance is a major issue both human and animal health, and resistant infections and resistance genes can be transmitted between animals and the humans who interact with them. One of the most urgent threats is Carbapenem-resistant Enterobacteriaceae (CRE). Antibiotic usage is a major risk factor for the development of fecal CRE carriage, which is both a source of bloodstream infection and spread to other susceptible patients through contact with hospital workers. Due to the lack of treatment options, these infections can be deadly in up to 50% of patients who acquire them. Current therapies to restore colonization resistance target the microbiota using fecal microbiota transplantation, prebiotics, or probiotics. However, for patients who must remain on antibiotics, these treatment options are unlikely to be successful. A healthy microbiota provides colonization resistance in two ways: by occupying all available niches in the intestine to directly prevent other microbiota from colonizing, and through modification of the intestinal environment to make it less welcoming for invading bacteria. The latter includes production of substances such as short-chain fatty acids, which allow the microbiota to interact with host cells and improve intestinal health and colonization resistance. The objective of this application is to devise a treatment to restore colonization resistance during antibiotic therapy that exploit the pathways used by the microbiota under homeostatic conditions. Our hypothesis is that 5-ASA, a drug that activates pathways in colonocytes used by the microbiota, will be successful at restoring colonization resistance against carbapenem resistance Enterobacteriaceae after antibiotic treatment in immunocompetent and immunocompromised hosts. To test our hypothesis, we will first use an SPF mouse model of antibiotic administration and CRE exposure with or without treatment with 5-ASA. Mice will be placed on a 5-ASA-containing diet either prior to CRE exposure (prevention) or after CRE infection (treatment) and colonization will be monitored through feces and cecal contents. We will then infect Germ-free mice recolonized with paired patient fecal samples collected before antibiotics are started and 4-7 days after antibiotic therapy is initiated. These mice will also be placed on a 5-ASA-containing diet to demonstrate that effective prevention or reduction of CRE colonization can be achieved in diverse patient microbiotas with various antibiotic therapies. Finally, we will utilize a cyclophosphamide model of immunosuppression in mice to demonstrate reduced CRE bacteremia as a result of 5-ASA-mediated reduction of intestinal CRE CFU. Successful completion of the proposed research will provide pre-clinical evidence that 5-ASA, a clinically approved drug, can be used to strengthen colonization resistance and lower the risk for CRE bacteremia in an immunocompromised host on antibiotic therapy by activating epithelial PPAR-g signaling, a paradigm shift that establishes the host as a treatment target for strengthening colonization resistance.