Understanding bacterial resistance to therapeutic phage cocktails in an animal model of infection

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The research is on bacteriophage (phage), viruses that specifically infect and kill bacterial cells, making phage therapy an exciting option to treat bacterial infections. With the growing threat of antibiotic resistance, there is considerable commercial and academic investment in phage therapy but hurdles still exist to its successful application in both humans and animals. While there has been incredible progress in understanding how bacteria resist phage predation under laboratory conditions, the importance of these processes during actual infections is unknown. This knowledge is critical to selection of phage in therapeutic cocktails that can work together to counter these bacterial defence systems. Our grouping has worked on the pathogenesis of Escherichia coli for over twenty years, understanding how specific strains cause different types of infection and we are now applying this knowledge to development of phage therapy which requires studying the interaction of phage with their target bacteria in the host during infection. The major focus of the research will be how the globally disseminated multi-drug resistant E. coli ST 131 resists phage treatment while infecting the mammalian bladder, and the work will build on three years of laboratory data including interactions in artificial urine. A key aspect of the project will be the application of a pig model of urinary tract infection in which the dynamics of phage predation and bacterial resistance can be studied. The PhD is 50% funded by Proteon Pharmaceuticals and they bring a wealth of expertise in phage therapy development to the research. We anticipate that the research will involve expression and sequence analysis of bacterial populations recovering from phage predation with a central theme of needing to understand bacterial population heterogeneity in the host during infection to select the most effective phage combinations. This work will run alongside other funded research developing phage interventions for UTI infections in dogs and E. coli O157 in the gastrointestinal tract of cattle. This project will benefit from world class facilities on campus including the Large Animal Research and Imaging Facility (LARIF) and the knowledge and resources provided by Proteon Pharmaceuticals, which has a platform to develop and commercialize phage-based products for animal and human health.