Stochastic variation and regulation of bacterial DNA repair and mutagenesis

The rapid evolution and spread of antibiotic resistance is a major threat to global health. It is rooted in the plasticity of bacterial genomes. There is growing evidence that the overuse of antibiotics not only promotes the spread of existing resistant genes, but also accelerates evolution of novel resistance mechanisms. Cellular stress and DNA damage responses appear to increase mutation rates during antibiotic treatment, but the molecular mechanisms remain unclear.

My research shows that mutation rates can vary between cells in a population, which may help a small fraction of cells to survive drug treatment and acquire genetic resistance. Conventional experiments on large cell populations cannot show the specific intracellular conditions that lead to a mutation in an individual cell. I will measure the movement of single proteins that repair DNA sequence errors inside living cells so I can identify mutation events under the microscope and map them to the genome sequence to identify the molecular processes that cause mutations.

These novel tools will show how antibiotic treatment speeds up the evolution of resistance. My research into the fundamental mechanisms of mutagenesis will also inform on equivalent processes in humans, where the accumulation of mutation leads to cancer.