Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used to combat inflammation, pain, and fever. New research shows how they may also be useful for killing bacterial pathogens (Chem. Biol. 2014, DOI: 10.1016/j.chembiol.2014.02.009). Inspired by preliminary data suggesting that NSAIDs might have antibacterial properties, a team of medicinal chemists led by Aaron J. Oakley of the University of Wollongong, in Australia, decided to investigate further. Testing a handful of NSAIDs, the team discovered that carprofen, bromfenac, and vedaprofen block the activity of an Escherichia coli DNA polymerase involved in DNA replication and repair. The team used X-ray crystallography to show that these NSAIDs bind to the subunit that clamps the polymerase onto DNA. The polymerase requires this subunit to recruit the other proteins that it needs to replicate and repair DNA. Although the antibacterial potency of these NSAIDs is still too weak to compete with existing antibiotics, several bacterial species have DNA-clamp structures similar to that of E. coli. The authors suggest that medicinal chemists might use this information to optimize the NSAID scaffold to create a more potent antibiotic.