Old Drugs To Treat Resistant Bugs: Methicillin-Resistant Staphylococcus aureus Isolates withmecCAre Susceptible to a Combination of Penicillin and Clavulanic Acid

Abstract

ABSTRACTβ-Lactam resistance in methicillin-resistantStaphylococcus aureus(MRSA) is mediated by the expression of an alternative penicillin-binding protein 2a (PBP2a) (encoded bymecA) with a low affinity for β-lactam antibiotics. Recently, a novel variant ofmecA, known asmecC, was identified in MRSA isolates from both humans and animals. In this study, we demonstrate thatmecC-encoded PBP2c does not mediate resistance to penicillin. Rather, broad-spectrum β-lactam resistance in MRSA strains carryingmecC(mecC-MRSA strains) is mediated by a combination of both PBP2c and the distinct β-lactamase encoded by theblaZgene of strain LGA251 (blaZLGA251), which is part ofmecC-encoding staphylococcal cassette chromosomemec(SCCmec) type XI. We further demonstrate thatmecC-MRSA strains are susceptible to the combination of penicillin and the β-lactam inhibitor clavulanic acidin vitroand that the same combination is effectivein vivofor the treatment of experimentalmecC-MRSA infection in wax moth larvae. Thus, we demonstrate how the distinct biological differences betweenmecA- andmecC-encoded PBP2a and PBP2c have the potential to be exploited as a novel approach for the treatment ofmecC-MRSA infections.