Development of Novel Bacteriophages Targeting Enteric Bacterial Pathogens

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Abstract This R21 proposal focuses on the development of novel therapeutics against enteric bacterial pathogens, specifically the Shigella species. The pathogens cause millions of infections and a staggering number of deaths around the globe each year despite advances such as clean water, sanitation, and oral rehydration therapy. Infection is due to bacterial invasion of the epithelial cells lining the gastrointestinal tract, and predominately occurs in children under the age of five years in developing countries. In industrialized nations, infections are linked to daycare center, foodborne, and waterborne outbreaks. Despite decades of research, there are no effective vaccines against Shigella. Furthermore, alarming increases in antibiotic resistance have complicated treatment. This proposal seeks to build upon recent findings to develop and evaluate pathogen-specific bacteriophages, viruses that infect bacteria, for future therapeutic development. The long-term goal of this project is to utilize bioengineering and synthetic biology to develop novel bacteriophages that can be used as therapeutic options to treat infectious diarrhea without harming the healthy commensal bacterial population of the gastrointestinal tract. The specific aims of this proposal are to first, utilize bioengineering to enhance our prototype bacteriophage and subsequently test the enhanced candidate for pathogen-specific lysis; and second, further engineer the prototype phage to expand the host range and delay the emergence of phage-resistant bacteria to circumvent common issues with natural bacteriophages. The proposed research includes the use of innovative approaches, technologies, and infection models that mimic the human-specific environment of the gastrointestinal tract. The proposal is further enhanced by a research team that combines the expertise of bacteriophage biology, bioengineering, bacterial pathogenesis, and mucosal biology, and organoid-derived infection models. Data obtained from the aims will lead to the development of novel therapeutics that could prove to be clinically effective in an age of rampant antimicrobial resistance and a lack of effective vaccines. 1