Supervisors: Emma Slack and Dr. Sarah Woodward

Polyketide synthases (pks) produce genotoxins such as colibactin in E. coli, which are thought to have evolved to enhance competitiveness within the crowded environment of the gut microbiome. However, a side-effect of colibactin production is DNA damage in the host epithelium, which can accelerate progression to colorectal cancer. Carriage of pks-positive E. coli strains has increased dramatically in westernized populations and is thought to be one factor driving the rise in early-onset colorectal cancer in these populations.

Based on our recent work, we will here develop vaccine-enhanced competition and gene-drive techniques to eliminate carriage of pks-producing E. coli from intact microbiomes. This project involves bioinformatic analysis of surface-antigen distributions of pks-positive E. coli found in the microbiomes of CRC patients, compared to pks-negative E. coli in the general population. Based on this information, we will design oral vaccines to target relevant antigens, potentially combined with CRISPR-based strategies to directly target pks genetic loci. These will be tested in in vivo models for their ability to suppress colibactin production and to prevent colon cancer development in in vivo models.

The project will span bacterial genomics, glycobiology, and vaccine design/mucosal immunology.