Microorganisms evolve quickly under selective conditions and can rapidly adapt to environmental changes. We recently discovered that transcription-coupled repair (TCR), and, encounters between the DNA replication and transcription machineries (conflicts) increase mutagenesis significantly in specific genes. We subsequently identified the factors required for these mutagenesis mechanisms. We now find that these factors promote antibiotic resistance development in bacteria. Here, using various experimental techniques, we plan to investigate the impact of TCR and conflicts on evolution of antibiotic resistance in important human pathogens, as well as deepen our understanding of the underlying mechanisms promoting this adaptive process. We are putting forth a research program with a novel approach to circumvent a global health crisis: a study tailored towards characterization of potential drug targets that promote evolution of antibiotic resistance in bacterial pathogens.
Elucidating the mechanisms driving microbial evolution and adaptation is critical for treatment of infectious disease, especially in the light of the emergence of drug-resistant pathogens. According to the CDC, antibiotic resistant bacteria are responsible for 2 million infections and 23,000 deaths in the US, each year, and these numbers are on the rise. This program investigates the mechanisms that bacterial pathogens utilize to promote adaptive mutations and epimutations in specific genes under selective conditions, with the ultimate goal of inhibiting pro-mutagenic mechanisms to block evolution of antibiotic resistance in the future.