Targeting Escherichia coli DNA double-strand break repair as an antibiotic re-sensitisation and anti-mutagenicity mechanism

The rise of bacterial resistance to antibiotics has evolved into a substantial global health challenge. The emergence of antibiotic-resistant bacterial strains, coupled with the sluggish development of new treatment options, presents a grave concern for healthcare. Projections indicate that by 2050, antibiotic resistance may contribute to a staggering 10 million deaths each year. In recent times, bacteria causing common infections have demonstrated resistance to antibiotics from all classes. Consequently, there is a demand for innovative antibiotics that explore novel mechanisms of action. To discover new drug targets, it is crucial to gain a comprehensive understanding of how bacteria combat and develop resistance to clinically used antibiotics. Investigating the mechanisms of the DNA damage response that facilitate antibiotic resistance may lead to the identification of potential new drug targets. This thesis aims to better understand the link between DNA repair and mutagenesis in Escherichia coli. The specific focus of the work described here is on the double-strand break repair (DSBR) pathway and how deficiencies in this pathway can have a myriad of effects on bacterial survival, population dynamics and eventually error-prone DNA polymerase V (pol V) formation.