Methicillin-resistant Staphylococcus aureus (MRSA) is becoming increasingly resistant to the most recently developed antibiotics. Now, Gonzales et al. identify a new potential therapy against multidrug-resistant MRSA comprising a combination of the clinically approved β-lactams meropenem, piperacillin and tazobactam (ME/PI/TZ). This triple combination acts synergistically to exhibit bacteriocidal activity against diverse MRSA strains in vitro and, owing to reciprocal collateral sensitivities of its components, suppresses the evolution of resistance. Notably, the triple therapy cleared a highly lethal MRSA infection in a mouse model as effectively as the more expensive monotherapy linezolid.