Engineering novel bacterial therapies for targeting microbes associated with chemotherapy response and toxicity

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Colorectal cancer (CRC) is the second leading cause of cancer related deaths world-wide. The gut microbiome is increasingly linked in the causation of this disease and strong stage-dependent correlations with the abundance of oral pathobionts and anti-correlations with mucosal commensal bacteria have been identified. There is emerging evidence that the microbiome is also able to influence therapeutic efficacy and toxicity in many established cytotoxic therapies. The implication of this is that the gut microbiome can be modulated to abrogate the toxicity of both immuno- and chemotherapy or improve its efficacy, and that it may even serve as a novel therapeutic target. However, current strategies for microbiome modification such as pre- and probiotic therapy, antibiotic therapy, faecal microbiota transplantation and microbial engineering have yet to be widely explored for therapeutic potential.Synthetic biology applies engineering principles and mathematical modelling to the development of new biotherapeutics. Bacteriocins are small antimicrobial peptides that are naturally produced by certain species of bacteria to target competitors and allow for the establishment of colonies. Nisin is the amongst the most studied and is used as a food preservative (E234). Bacteriocins can be highly specific or have a broad spectrum and can be combined in a modular fashion to create unique antimicrobial agents. Our hypothesis is that bacteriocins can be used for precision engineering of the CRC mucosal microbiome to influence the efficacy and toxicity of cytotoxic chemotherapy. The tools of synthetic biology will enable the rapid engineering of strains to target specific bacterial species. We deploy these therapies in a number of model systems with an aim to providing the foundation for future clinical trials. This engineering approach will facilitate the development of interventions that can be co-delivered with chemotherapy agents, allowing for a reduction in toxicity, a safe increase in dose, and ultimately improve efficacy.