Engineered phage for expanded host range and increased payload capacity

The rapid rise of antimicrobial resistance has resulted in renewed interest in alternative strategies to control the spread of pathogens including multidrug resistant ones. Phage (virus that infects and kills bacteria) therapy has gathered renewed interest as a viable alternative to antibiotics but selection and production of phages for biomedical applications to prevent or treat bacterial infections in humans and animals remains a challenging task. Current solutions can involve a complex cocktail of different phages to produce efficient results. Consequently, genetic engineering approaches are now being explored to optimize phage anti-microbial activity, e.g. by use of phages as CRISPR-Cas delivery vehicles, and address problems such as the narrow host range of individual phages that limit broader use as effective therapeutic interventions.

The project aims to create novel, engineered bacteriophages that will improve or add desired traits for therapeutic use by combining computational (i.e., artificial intelligence) with molecular genetic/synthetic biology approaches. Mining large, publicly available datasets using computational/bioinformatic tools will identify phage receptor variants and phage anti-defence systems that can be screened and assessed for functionality. Individual elements displaying favourable characteristics will be used to rationally design and genetically assemble novel phages with enhanced properties such as improved host range and infectious potential. Integration of additional modules encoding genetic payloads such as CRISPR-Cas systems with the potential to further increase efficacy of the modified phages will require the construction of minimal phage genomes able to accommodate the added genetic material. The selected phage(s) will be subjected to several rounds of genome reduction to determine the minimal viable genome(s) that will be used to re-assemble modified phages integrating the payload module.