Strategic re-engineering of antibiotics

Multidrug-resistant bacteria, especially those that defy even last-resort antibiotics, are causing a global health crisis fuelled by antibiotic overuse and misuse as well as the lack of development of new antibiotics. Multidrug-resistant bacteria compromise our ability to effectively treat infections, affecting medical procedures such as surgeries and cancer treatments while increasing illness duration, mortality rates and healthcare costs. In this Review, we discuss re-engineering approaches for existing antibiotics to address multidrug-resistant bacterial infections. We outline how antibiotic activity against drug-resistant bacteria can be increased through structural modifications and by engineering polyvalent drugs and combination therapies designed to overcome drug-resistance mechanisms. Finally, we examine the regulatory and translational challenges for antibiotic re-engineering, highlighting the need for antibiotic stewardship and global guidelines.