The Tate group have published a paper targeting antibiotic resistance through development of a potent small-molecule inhibitor of bacterial DNA repair

Antibiotic resistance is one of the most serious threats to health globally. Both the use and misuse of antibiotics promotes the emergence of resistance, and there are now bacteria such as methicillin-resistant staphylococcus aureus (MRSA) that are resistant to many major antibiotics. There is therefore an urgent need for new molecules that can target bacteria through novel mechanisms of action.

The Tate group are undertaking research to address this challenge, and in a new paper in Bioorganic and Medicinal Chemistry developed a high potency small-molecule, IMP-1700, that sensitizes MRSA to antibiotics where resistance has emerged. IMP-1700 inhibits the bacteria’s ability to repair breaks in its DNA, which amplifies the effects of DNA-damaging antibiotics and also decreases the bacterial ‘SOS’ response which promotes mutations during DNA repair. This may therefore reverse antibiotic resistance and also decrease the rate of emergence of resistance. In addition, it is envisaged that such inhibitors could be used to promote immune clearance of infections by increasing the effect of bacterial DNA damage resulting from attack by the immune system, thus leaving healthy gut bacteria unaffected. IMP-1700 will serve as an important tool for future studies to validate DNA repair as a drug target in antimicrobial resistance.

Work within the Tate group was conducted by three members of the Imperial MRes in Drug Discovery and Development course; first author Carine Lim, and co-authors Leigh-Anne Gavin and Declan Cook. The project was conducted with support from MRes Cohort Managers Dr Jennie Hutton and Dr Charlotte Sutherell, and supervised by senior author Dr Tom Lanyon Hogg.

This work was performed in collaboration with the group of Dr Andrew Edwards and senior author Dr Lindsay Evans in the Department of Infectious Disease, and was supported by awards from the EMBRACE network and the Imperial Confidence in Concept scheme.