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Novel mutations in penicillin-binding protein genes in clinical Staphylococcus aureus isolates that are methicillin resistant on susceptibility testing, but lack the mec gene

Holmes, M. A.; Parkhill, J.; Peacock, S. J.; Skov, R. L.; Ba, X.; Petersen, A.; Larsen, A. R.; Holden, M. T. G.; Edwards, G. F.; Harrison, E. M.; Ba, Xiaoliang; Harrison, Ewan M.; Edwards, Giles F.; Holden, Matthew T. G.; Holden, Matthew T.G.; Larsen, Anders Rhod; Petersen, Andreas; Skov, Robert L.; Peacock, Sharon J.; Parkhill, Julian; Paterson, Gavin K.; Holmes, Mark A.


M. A. Holmes

J. Parkhill

S. J. Peacock

R. L. Skov

X. Ba

A. Petersen

A. R. Larsen

M. T. G. Holden

G. F. Edwards

E. M. Harrison

Xiaoliang Ba

Ewan M. Harrison

Giles F. Edwards

Matthew T. G. Holden

Matthew T.G. Holden

Anders Rhod Larsen

Andreas Petersen

Robert L. Skov

Sharon J. Peacock

Julian Parkhill

Gavin K. Paterson

Mark A. Holmes


Objectives: Methicillin-resistant Staphylococcus aureus (MRSA) is an important global health problem. MRSA resistance to β-lactam antibiotics is mediated by the mecA or mecC genes, which encode an alternative penicillin binding protein (PBP)2a that has a low affinity to β-lactam antibiotics. Detection of mec genes or PBP2a is regarded as the gold standard for the diagnosis of MRSA.We identified four MRSA isolates that lacked mecA or mecC genes, but were still phenotypically resistant to encillinase-resistant β-lactam antibiotics. Methods: The four human S. aureus isolates were investigated by whole genome sequencing and a range of phenotypic assays. Results: We identified a number of amino acid substitutions present in the endogenous PBPs 1, 2 and 3 that were found in the resistant isolates but were absent in closely related susceptible isolates and which maybe the basis of resistance. Of particular interest are three identical amino acid substitutions in PBPs 1, 2 and 3, occurring independently in isolates from at least two separate multilocus sequence types. Two different non-conservative substitutions were also present in the same amino acid of PBP1 in two isolates from two different sequence types. Conclusions: This work suggests that phenotypically resistant MRSA could be misdiagnosed using molecular methods alone and provides evidence of alternative mechanisms for β-lactam resistance in MRSA that may need to be considered by diagnostic laboratories.


Ba, X., Harrison, E. M., Edwards, G. F., Holden, M. T., Larsen, A. R., Petersen, A., …Holmes, M. A. (2014). Novel mutations in penicillin-binding protein genes in clinical Staphylococcus aureus isolates that are methicillin resistant on susceptibility testing, but lack the mec gene. The journal of antimicrobial chemotherapy, 69(3), 594-597.

Journal Article Type Article
Acceptance Date Sep 26, 2013
Online Publication Date Nov 11, 2013
Publication Date Mar 1, 2014
Deposit Date Jun 23, 2015
Publicly Available Date Jun 23, 2015
Journal Journal of antimicrobial chemotherapy
Print ISSN 0305-7453
Electronic ISSN 1460-2091
Publisher Oxford University Press
Peer Reviewed Peer Reviewed
Volume 69
Issue 3
Pages 594-597
Keywords β-lactams, MRSA, mecA, mecC
Public URL
Publisher URL
Additional Information Copy of article first published in: Journal of antimicrobial chemotherapy, 2014, v.69, issue 3


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© The Authors 2013. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( 3.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.

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