Old drugs to treat resistant bugs: Methicillin-resistant Staphylococcus aureus isolates with mecC are susceptible to a combination of penicillin and clavulanic acid

Ba, Xiaoliang; Harrison, Ewan M.; Lovering, Andrew L.; Gleadall, Nicholas; Zadoks, Ruth; Parkhill, Julian; Peacock, Sharon J.; Holden, Matthew T. G.; Paterson, Gavin K.; Holmes, Mark A.

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 (blaZLGA251), which is part of mecC-encoding staphylococcal cassette chromosome mec (SCCmec) 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.

Citation

Ba, X., Harrison, E. M., Lovering, A. L., Gleadall, N., Zadoks, R., Parkhill, J., …Holmes, M. A. (2015). Old drugs to treat resistant bugs: Methicillin-resistant Staphylococcus aureus isolates with mecC are susceptible to a combination of penicillin and clavulanic acid. Antimicrobial agents and chemotherapy, 59(12), 7396-7404. https://doi.org/10.1128/AAC.01469-15

• Journal Article Type: Article
• Acceptance Date: Sep 3, 2015
• Online Publication Date: Sep 21, 2015
• Publication Date: Dec 1, 2015
• Deposit Date: Dec 8, 2015
• Publicly Available Date: Nov 23, 2017
• Journal: Antimicrobial agents and chemotherapy
• Print ISSN: 0066-4804
• Electronic ISSN: 1098-6596
• Publisher: American Society for Microbiology
• Peer Reviewed: Peer Reviewed
• Volume: 59
• Issue: 12
• Pages: 7396-7404
• DOI: https://doi.org/10.1128/AAC.01469-15
• Keywords: β-lactams, MRSA, mecC
• Public URL: https://hull-repository.worktribe.com/output/382218
• Publisher URL: http://aac.asm.org/content/59/12/7396.abstract?sid=c132dcf3-0c8a-419b-b3c9-a00b500bff8f
• Additional Information: Copy of article first published in: Antimicrobial agents and chemotherapy, 2015, v.59, issue 12