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JAC Advance Access originally published online on October 3, 2008
Journal of Antimicrobial Chemotherapy 2008 62(6):1215-1221; doi:10.1093/jac/dkn417
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© The Author 2008. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Original research

Reversal of methicillin resistance in Staphylococcus aureus by thioridazine

Janne K. Klitgaard1,2,*, Marianne N. Skov1, Birgitte H. Kallipolitis2 and Hans Jørn Kolmos1

1 Department of Clinical Microbiology, Institute of Clinical Research, University of Southern Denmark, Odense University Hospital, Odense, Denmark 2 Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark

Received 2 July 2008; returned 21 August 2008; revised 9 September 2008; accepted 11 September 2008

* Correspondence address. Department of Biochemistry and Molecular Biology, University of Southern Denmark, Campusvej 55, DK-5230 Odense M, Denmark. Tel: +45-6550-2423; Fax: +45-6550-2467; E-mail: jkklitgaard{at}health.sdu.dk

Objectives: Thioridazine has been shown to reverse oxacillin resistance in methicillin-resistant Staphylococcus aureus (MRSA) in vitro. The aim of this study was to investigate whether thioridazine alone or in combination with oxacillin affects the transcription of the methicillin resistance gene mecA and the protein level of the encoded protein PBP2a.

Methods: Viability of MRSA was determined in liquid media in the presence of oxacillin or thioridazine alone or in combination. Transcription of mecA was analysed by primer extension, and the protein level of PBP2a was analysed by western blotting in the presence of thioridazine and oxacillin.

Results: We observed an increased susceptibility of MRSA towards oxacillin in the presence of thioridazine compared with bacteria grown with oxacillin or thioridazine alone. Transcription of mecA was reduced with increasing concentrations of thioridazine in the presence of a fixed amount of oxacillin. Furthermore, the protein level of PBP2a was reduced when bacteria were treated with the combination of oxacillin and thioridazine. The two drugs also affected the mRNA level of the β-lactamase gene, blaZ.

Conclusions: The present study indicates that reversal of methicillin resistance by thioridazine in MRSA may be explained by a reduced transcription of mecA and blaZ, resulting in a reduced protein level of PBP2a.

Keywords: MRSA , phenothioazine , mecA , PBP2a


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