Combination of thioridazine and dicloxacillin combats Methicillin-resistant Staphylococcus aureus infections in Caenorhabditis elegans.

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  • Marianne Ø Poulsen, University of Southern Denmark, Denmark
  • Lone Vedel Schøler, Denmark
  • Anette Nielsen, University of Southern Denmark, Denmark
  • Marianne N Skov, University of Southern Denmark, Denmark
  • Hans Jørgen Kolmos, University of Southern Denmark, Denmark
  • Birgitte H Kallipolitis, University of Southern Denmark, Denmark
  • Anders Olsen, Denmark
  • Janne K Klitgaard, University of Southern Denmark, Denmark
The shortage of drugs active against meticillin-resistant Staphylococcus aureus (MRSA) is a growing clinical problem. In vitro studies indicate that the phenothiazine thioridazine (TZ) might enhance the activity of the β-lactam antibiotic dicloxacillin (DCX) to a level where MRSA is killed, but experiments in simple animal models have not been performed. In the present study, we introduced Caenorhabditis elegans infected by S. aureus as an in vivo model to test the effect of TZ as a helper drug in combination with DCX. Because TZ is an anthelmintic, initial experiments were carried out to define the thresholds of toxicity, determined by larval development, and induction of stress-response markers. No measurable effects were seen at concentrations of less than 64 mg TZ l−1. Seven different MRSA strains were tested for pathogenicity against C. elegans, and the most virulent strain (ATCC 33591) was selected for further analyses. In a final experiment, full-grown C. elegans were exposed to the test strain for 3 days and subsequently treated with 8 mg DCX l−1 and 8 mg TZ l−1 for 2 days. This resulted in a 14-fold reduction in the intestinal MRSA load as compared with untreated controls. Each drug alone resulted in a two- to threefold reduction in MRSA load. In conclusion, C. elegans can be used as a simple model to test synergy between DCX and TZ against MRSA. The previously demonstrated in vitro synergy can be reproduced in vivo
Original languageEnglish
JournalJournal of Medical Microbiology
Volume63
Issue9
Pages (from-to)1174-1180
Number of pages7
ISSN0022-2615
DOIs
Publication statusPublished - 9 Jun 2014

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