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Thioridazine as an antibiotic potentiator

Collaborators

Associate Professor Janne Kudsk Klitgaard
Professor Birgitte H. Kallipolitis
Professor Hans Jørn Kolmos
Associate Professor Thomas Emil Andersen
Molecular Biologist Marianne N. Skov

Project description

Many strains are multi-drug resistant and there is a shortage of active drugs because of slow process in developing new antibiotics. Therefore, there is an urgent need for new strategies to manage MRSA.

Thioridazine (TDZ) is an antipsychotic drug with antibacterial effects. When combined with conventional antibiotics, the compounds work in synergy with killing of MRSA as a result (1).

We study the anti-bacterial effect of thioridazine on MRSA and in combination with the β-lactam antibiotic dicloxacillin (DCX). Ultimately, our goal is to understand the mechanism of action for the combination of thioridazine and DCX at the molecular level. We have investigated the effect of TDZ and DCX on S. aureus which is impaired in cell wall biosynthesis and in maintaining the membrane potential (2, 3), but the mechanism is not yet fully elucidated.

Furthermore, we have demonstrated an in vivo effect in the nematode C. elegans and in a peritonitis model in mice (4, 5). In a porcine model, the combination of TDZ and DCX could not eradicate an aortic graft infection indicating that the combination treatment is not suited for systemic treatment (6). However, in the same porcine model, TDZ and DCX could inhibit a device-associated Staphylococcus aureus infection (7).

Funded by

Forum of Health science in Southern Denmark, The Danish medical research council (2006-5), Science Trust Odense University Hospital, The Lundbeck Foundation (R32-A2819, 2013-13618, 2014-2664), The Novo Nordic Foundation, Brødrene Hartmanns Foundation, Aase & Ejnar Danielsens Foundation, The Danish Heart Foundation (14-R97-A5266), Innovation Fund Denmark (52-2014-1), Research Council at Odense University Hospital (R15-A929-B176), The Danish Agriculture & Food Council (132337), TrygFonden (7-11-1210), Fionia Fond

 

References

1. Klitgaard J, Skov M, Kallipolitis B, Kolmos H. Reversal of methicillin resistance in Staphylococcus aureus by thioridazine. Journal of Antimicrobial Chemotherapy. 2008;62(6):1215-21.

2. Thorsing M, Klitgaard JK, Atilano ML, Skov MN, Kolmos HJ, Filipe SR, et al. Thioridazine Induces Major Changes in Global Gene Expression and Cell Wall Composition in Methicillin-Resistant Staphylococcus aureus USA300. Plos One. 2013;8(5).

3. Wassmann CS, Lund LC, Thorsing M, Lauritzen SP, Kolmos HJ, Kallipolitis BH, et al. Molecular mechanisms of thioridazine resistance in Staphylococcus aureus. PloS one. 2018;13(8):e0201767.

4. Poulsen MO, Scholer L, Nielsen A, Skov MN, Kolmos HJ, Kallipolitis BH, et al. Combination therapy with thioridazine and dicloxacillin combats meticillin-resistant Staphylococcus aureus infection in Caenorhabditis elegans. Journal of Medical Microbiology. 2014;63:1174-80.

5. Stenger M, Hendel K, Bollen P, Licht PB, Kolmos HJ, Klitgaard JK. Assessments of Thioridazine as a Helper Compound to Dicloxacillin against Methicillin-Resistant Staphylococcus aureus: In Vivo Trials in a Mouse Peritonitis Model. Plos One. 2015;10(8).

6. Stenger M, Behr-Rasmussen C, Klein K, Gronnemose RB, Andersen TE, Klitgaard JK, et al. Systemic thioridazine in combination with dicloxacillin against early aortic graft infections caused by Staphylococcus aureus in a porcine model: In vivo results do not reproduce the in vitro synergistic activity. Plos One. 2017;12(3).

7. Stenger M, Klein K, Grønnemose R, Klitgaard J, Kolmos H, Lindholt J, et al. Co-release of dicloxacillin and thioridazine from catheter material containing an interpenetrating polymer network for inhibiting device-associated Staphylococcus aureus infection. Journal of Controlled Release. 2016;241:125–34.

 

 

Contact person

Janne Kudsk Klitgaard, Associate Professor at the Department of Clinical Research and the Department of Biochemistry and Molecular Biology

Contact

Last Updated 12.03.2020