DNA double-strand break formation and repair as targets for novel antibiotic combination chemotherapy

An unrepaired DNA double-strand break (DSB) is lethal to cells. In bacteria, DSBs are usually repaired either via an error-prone pathway, which ligates the ends of the break or an accurate recombination pathway. Due to this lethality, drugs that induce persistent DSBs have been successful in bacterial infection treatment. However, recurrent usage of these drugs has led to emergence of resistant strains. Several articles have thoroughly reviewed the causes, mechanisms and effects of bacterial drug resistance while others have also discussed approaches for facilitating drug discovery and development. Here, we focus on a hypothetical chemotherapeutic strategy that can be explored for minimizing development of resistance to novel DSB-inducing compounds. We also highlight the possibility of utilizing bacterial DSB repair pathways as targets for the discovery and development of novel antibiotics. Lay abstract Our health systems face a huge challenge in the form of antimicrobial resistance, which may result in many common infections becoming untreatable. The same antibiotics that gave modern medicine its power are fast losing their hold on the germs that cause disease. Many options are being developed to restore the control that antibiotics have on the microbes that cause many diseases. In this perspective, we outline a concept that is built around the way and manner in which bacteria mend their DNA whenever there is a break in the DNA chain. We discuss the merits of finding a new class of drugs that obstruct bacterial ability to mend their broken DNA. In this scenario, a combination of these new drugs with existing drugs or other new drugs that cause breaks in bacterial DNA would become a powerful therapeutic regimen. This concept, when fully developed, will offer hope in our effort to combat antimicrobial-resistant infections.