Resistance to antibiotics is a global threat to public health. It is estimated that by 2050, 10 million people will die annually of resistant infections. To combat this looming prospect we need to restock our arsenal of effective antibiotics. Unfortunately, all conventional approaches for antibiotic discovery have failed. Here, we propose a radically-different approach. We will exploit antibiotic targets that have been historically underexplored. By designing an innovative fluorescent assay that reports on target engagement, we will screen a large library for antibiotic activity against these unexplored targets. We expect to discover potent antibiotics with a completely new mechanism-of-action.