The superbug methicillin-resistant Staphylococcusaureus (MRSA) is a leading cause of hospital infections. Serge Van Calenbergh of Ghent University and coworkers have now developed a potentiator that helps overcome MRSA resistance to antibiotics by disrupting quorum sensing (Angew. Chem. Int. Ed. 2016, DOI: 10.1002/anie.201601973). Potentiators are agents that boost the sensitivity of microbes to existing drugs, and quorum sensing is a communication system bacteria use to regulate virulence. To find a potentiator for anti-MRSA drugs, Van Calenbergh and coworkers started with hamamelitannin, a natural product from witch hazel. Hamamelitannin potentiates anti-MRSA agents by modulating quorum sensing but is weakly active and metabolically unstable. The researchers synthesized 58 analogs designed to have better drug properties. When the best of these analogs was administered with the antibiotic cephalexin to infected mice, it killed MRSA about five times as potently as hamamelitannin combined with cephalexin and about 100 times as well as cephalexin alone. The group is currently collaborating with Elanco Animal Health to examine the use of an optimized compound to treat mastitis, a MRSA infection of breast tissue, in cattle.