title: Old Drugs To Treat Resistant Bugs: Methicillin-Resistant Staphylococcus aureus Isolates with mecC Are Susceptible to a Combination of Penicillin and Clavulanic Acid.
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.
authors.affiliation: Department of Veterinary Medicine, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Xiaoliang
authors.initials: X
authors.lastname: Ba
authors.affiliation: Department of Veterinary Medicine, University of Cambridge, Cambridge, United Kingdom eh439@cam.ac.uk.
authors.forename: Ewan M
authors.identifier: http://orcid.org/0000-0003-2720-0507
authors.initials: EM
authors.lastname: Harrison
authors.affiliation: Institute of Microbiology and Infection and School of Biosciences, University of Birmingham, Birmingham, United Kingdom.
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Lovering
authors.affiliation: Department of Veterinary Medicine, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Gleadall
authors.affiliation: Moredun Research Institute, Penicuik, United Kingdom Institute of Biodiversity, Animal Health and Comparative Medicine, University of Glasgow, Glasgow, United Kingdom.
authors.forename: Ruth
authors.initials: R
authors.lastname: Zadoks
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, United Kingdom.
authors.forename: Julian
authors.identifier: http://orcid.org/0000-0002-7069-5958
authors.initials: J
authors.lastname: Parkhill
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, United Kingdom University of Cambridge, Department of Medicine, Cambridge, United Kingdom.
authors.forename: Sharon J
authors.initials: SJ
authors.lastname: Peacock
authors.affiliation: University of St. Andrews, School of Medicine, St. Andrews, United Kingdom.
authors.forename: Matthew T G
authors.initials: MT
authors.lastname: Holden
authors.affiliation: University of Hull, School of Biological, Biomedical and Environmental Sciences, Hull, United Kingdom.
authors.forename: Gavin K
authors.initials: GK
authors.lastname: Paterson
authors.affiliation: Department of Veterinary Medicine, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Holmes
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics; D019818:Clavulanic Acid / Q000494:pharmacology*; D004347:Drug Interactions; D024881:Drug Resistance, Bacterial / Q000187:drug effects*; D007814:Larva / Q000187:drug effects / Q000382:microbiology; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects* / Q000235:genetics / Q000302:isolation & purification; D008826:Microbial Sensitivity Tests; D009036:Moths / Q000187:drug effects / Q000382:microbiology; D009154:Mutation; D010403:Penicillin Resistance / Q000187:drug effects / Q000235:genetics; D046915:Penicillin-Binding Proteins / Q000235:genetics*; D010406:Penicillins / Q000494:pharmacology*; D065093:beta-Lactamase Inhibitors / Q000494:pharmacology; D001618:beta-Lactamases / Q000235:genetics
chemical_list: D001426:Bacterial Proteins; D046915:Penicillin-Binding Proteins; D010406:Penicillins; D065093:beta-Lactamase Inhibitors; C487789:mecA protein, Staphylococcus aureus; D019818:Clavulanic Acid; D001618:beta-Lactamases