Bacterial resistance to existing antibiotics is now recognised as a major global health threat. It has been estimated that by the year 2050, 10 million lives per annum may be at risk due to drug-resistant infections. Urgent action and new approaches to combat this serious threat are imperative. Bacterial infections are most commonly treated using beta-lactam antibiotics. The production of extended spectrum beta-lactamases, which hydrolyse all beta-lactams except carbapenems, is a significant mechanism of resistance that impedes the treatment of infection. Of particular concern is the recent emergence of carbapenemases, beta-lactamases that degrade all beta-lactams including carbapenems, the “drugs of last resort” to treat multi-drug resistant bacterial infections. This project will utilise our detailed chemical reaction-mapping technique to design highly potent inhibitors of clinically important beta-lactamases. This will provide therapies to tackle the underlying mechanisms of resistance and facilitate the use of combination therapies for the treatment of infectious disease.