title: Combination therapy with thioridazine and dicloxacillin combats meticillin-resistant Staphylococcus aureus infection in Caenorhabditis elegans.
abstract: 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.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark.|Institute of Clinical Research, Research Unit of Clinical Microbiology, University of Southern Denmark, Odense, Denmark.
authors.forename: Marianne Ø
authors.initials: MØ
authors.lastname: Poulsen
authors.affiliation: Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark.
authors.forename: Lone
authors.initials: L
authors.lastname: Schøler
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark.
authors.forename: Anette
authors.initials: A
authors.lastname: Nielsen
authors.affiliation: Institute of Clinical Research, Research Unit of Clinical Microbiology, University of Southern Denmark, Odense, Denmark.
authors.forename: Marianne N
authors.initials: MN
authors.lastname: Skov
authors.affiliation: Institute of Clinical Research, Research Unit of Clinical Microbiology, University of Southern Denmark, Odense, Denmark.
authors.forename: Hans Jørn
authors.initials: HJ
authors.lastname: Kolmos
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark.
authors.forename: Birgitte H
authors.initials: BH
authors.lastname: Kallipolitis
authors.affiliation: Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark.
authors.forename: Anders
authors.initials: A
authors.lastname: Olsen
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark.|Institute of Clinical Research, Research Unit of Clinical Microbiology, University of Southern Denmark, Odense, Denmark.
authors.forename: Janne K
authors.initials: JK
authors.lastname: Klitgaard
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage*; D058491:Bacterial Load; D017173:Caenorhabditis elegans / Q000382:microbiology*; D004009:Dicloxacillin / Q000008:administration & dosage*; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination / Q000379:methods; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects*; D013203:Staphylococcal Infections / Q000188:drug therapy; D013881:Thioridazine / Q000008:administration & dosage*; D016896:Treatment Outcome
chemical_list: D000900:Anti-Bacterial Agents; D004009:Dicloxacillin; D013881:Thioridazine