Multidrug-resistant bacteria, especially those that defy even last-resort antibiotics, are causing a global health crisis fueled by antibiotic overuse and misuse as well as the lack of new antibiotic development. Multidrug-resistant bacteria compromise our ability to effectively treat infections, impacting medical procedures like surgeries and cancer treatments while increasing illness duration, mortality rates and healthcare costs. In this Review, we discuss reengineering 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 regulatory and translational challenges for antibiotic reengineering, highlighting the need for antibiotic stewardship and global guidelines.