Grant: CIHR Fellowship

Microbial communities within humans are thought to impart considerable environmental influence on health and diseases. Molecules derived from bacteria are key to deciphering the roles microbes have in this relationship. Colibactin, is a cancer-linked, DNA-damaging agent made by certain gut bacteria, including many gut commensal E. coli. Bacteria that produce colibactin can damage DNA in human cells and are linked to colorectal cancer. This raises questions whether other gut bacteria make yet-uncharacterized DNA damaging agents or mediate other interactions within the community affecting cancer development. Here, I propose to uncover novel bacterial genotoxins in the human microbiome and investigate their DNA damage capability. Aim 1 describes how I curate the collection of genes encoding the assembly bioactive molecules. I use the presence of DNA repair and maintenance enzymes that protect the organism from its own cytotoxic compounds to identify potential genotoxins. Aim 2 outlines multiple approaches that will be used to rapidly access and synthesize these molecules, while Aim 3 determines potential toxic activity of the molecules in human cells. Molecules damaging either DNA or block the normal cell cycle are candidates for future animal studies to determine the contributions the producing gut bacteria have in cancer development.