Even when antibiotics pummel a bacterial infection, a small population of the pathogen hunkers down and hibernates, thereby avoiding total destruction. After some time, these so-called persistent bacteria flare up and are responsible for the chronic infections found in patients, such as those with implanted medical devices. Researchers led by Kim Lewis of Northeastern University report that molecules with acyldepsipeptide architectures can kill persistent pathogens such as Staphylococcus aureus when used in combination with rifampicin, ciprofloxacin, or other common antibiotics (Nature 2013, DOI: 10.1038/nature12790). Those drugs typically kill growing cells by targeting the cells’ replication biomachinery. But hibernating bacteria aren’t replicating and thus escape. Lewis’s team found that an acyldepsipeptide molecule, ADEP 4, can activate cellular machinery called proteases, which chop up proteins. ADEP 4 causes proteases to open wide and break down proteins unselectively, causing persistent bacteria to digest their own cells. Bacteria could easily evolve resistance to ADEP 4 if it were used alone. But as the team shows, the pair of antibiotics clears infections—including persistent bacteria—in mice.