ABSTRACT β-Lactam resistance in methicillin-resistant Staphylococcus aureus (MRSA) is mediated by the expression of an alternative penicillin-binding protein 2a (PBP2a) (encoded by mecA ) with a low affinity for β-lactam antibiotics. Recently, a novel variant of mecA , known as mecC , was identified in MRSA isolates from both humans and animals. In this study, we demonstrate that mecC -encoded PBP2c does not mediate resistance to penicillin. Rather, broad-spectrum β-lactam resistance in MRSA strains carrying mecC ( mecC -MRSA strains) is mediated by a combination of both PBP2c and the distinct β-lactamase encoded by the blaZ gene of strain LGA251 ( blaZ _LGA251 ), which is part of mecC -encoding staphylococcal cassette chromosome mec (SCC mec ) type XI. We further demonstrate that mecC -MRSA strains are susceptible to the combination of penicillin and the β-lactam inhibitor clavulanic acid in vitro and that the same combination is effective in vivo for the treatment of experimental mecC -MRSA infection in wax moth larvae. Thus, we demonstrate how the distinct biological differences between mecA - and mecC -encoded PBP2a and PBP2c have the potential to be exploited as a novel approach for the treatment of mecC -MRSA infections.