<abstract xmlns="http://www.w3.org/1999/xhtml"><p>This study explored a potential treatment against methicillin-resistant <italic>Staphylococcus aureus</italic> (MRSA) infections that combines thioridazine (TZ), an efflux pump inhibitor, and miconazole (MCZ), an autolysis inducer, with the anti-microbial drug cloxacillin (CXN). <italic>In vitro</italic>, the combination treatment of TZ and MCZ significantly reduced 4096-fold (Σ (FIC) = 0.1 – 1.25) the MIC value of CXN against <italic>S. aureus</italic>. <italic>In vivo</italic>, the combination therapy significantly relieved breast redness and swelling in mice infected with either clinical or standard strains of <italic>S. aureus</italic>. Meanwhile, the number of bacteria isolated from the MRSA135-infected mice decreased significantly (<italic>p</italic> = 0.0427 &lt; 0.05) after the combination therapy when compared to monotherapy. Moreover, the number of bacteria isolated from the mice infected with a reference <italic>S. aureus</italic> strain also decreased significantly (<italic>p</italic> = 0.0191 &lt; 0.05) after the combination therapy when compared to monotherapy. The pathological changes were more significant in the CXN-treated group when compared to mice treated with a combination of three drugs. In addition, we found that combination therapy reduced the release of the bacteria-stimulated cytokines such as IL-6, IFN-γ, and TNF-α. Cytokine assays in serum revealed that CXN alone induced IL-6, IFN-γ, and TNF-α in the mouse groups infected with ATCC 29213 or MRSA135, and the combination of these three drugs significantly reduced IL-6, IFN-γ, and TNF-α concentrations. Also, the levels of TNF-α and IFN-γ in mice treated with a combination of three drugs were significantly lower than in the CXN-treated group. Given the synergistic antibacterial activity of CXN, we concluded that the combination of CXN with TZ, and MCZ could be developed as a novel therapeutic strategy against <italic>S. aureus.</italic></p></abstract>

This study explored a potential treatment against methicillin-resistant Staphylococcus aureus (MRSA) infections that combines thioridazine (TZ), an efflux pump inhibitor, and miconazole (MCZ), an autolysis inducer, with the anti-microbial drug cloxacillin (CXN). In vitro, the combination treatment of TZ and MCZ significantly reduced 4096-fold (Σ (FIC) = 0.1 – 1.25) the MIC value of CXN against S. aureus. In vivo, the combination therapy significantly relieved breast redness and swelling in mice infected with either clinical or standard strains of S. aureus. Meanwhile, the number of bacteria isolated from the MRSA135-infected mice decreased significantly (p = 0.0427 < 0.05) after the combination therapy when compared to monotherapy. Moreover, the number of bacteria isolated from the mice infected with a reference S. aureus strain also decreased significantly (p = 0.0191 < 0.05) after the combination therapy when compared to monotherapy. The pathological changes were more significant in the CXN-treated group when compared to mice treated with a combination of three drugs. In addition, we found that combination therapy reduced the release of the bacteria-stimulated cytokines such as IL-6, IFN-γ, and TNF-α. Cytokine assays in serum revealed that CXN alone induced IL-6, IFN-γ, and TNF-α in the mouse groups infected with ATCC 29213 or MRSA135, and the combination of these three drugs significantly reduced IL-6, IFN-γ, and TNF-α concentrations. Also, the levels of TNF-α and IFN-γ in mice treated with a combination of three drugs were significantly lower than in the CXN-treated group. Given the synergistic antibacterial activity of CXN, we concluded that the combination of CXN with TZ, and MCZ could be developed as a novel therapeutic strategy against S. aureus.

Inhibition of Drug Resistance of <italic>Staphylococcus aureus</italic> by Efflux Pump Inhibitor and Autolysis Inducer to Strengthen the Antibacterial Activity of β-lactam Drugs

Polish Journal of Microbiology

This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

Inhibition of Drug Resistance of  by Efflux Pump Inhibitor and Autolysis Inducer to Strengthen the Antibacterial Activity of β-lactam Drugs

This study explored a potential treatment against methicillin-resistant Staphylococcus aureus (MRSA) infections that combines thioridazine (TZ), an efflux pump...

Inhibition of Drug Resistance of Staphylococcus aureus by Efflux Pump Inhibitor and Autolysis Inducer to Strengthen the Antibacterial Activity of β-lactam Drugs

Article Category: original-paper

Published Online: Dec 05, 2019

Page range: 477 - 491

Received: Jun 20, 2019

Accepted: Sep 21, 2019

DOI: https://doi.org/10.33073/pjm-2019-047

Keywords
mastitis, thioridazine (TZ), miconazole (MCZ), cloxacillin (CXN), combination therapy

© 2019 Wenjing Luan et al., published by Sciendo

This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

Inhibition of Drug Resistance of Staphylococcus aureus by Efflux Pump Inhibitor and Autolysis Inducer to Strengthen the Antibacterial Activity of β-lactam Drugs

Article Category: original-paper

Published Online: Dec 05, 2019

Page range: 477 - 491

Received: Jun 20, 2019

Accepted: Sep 21, 2019

DOI: https://doi.org/10.33073/pjm-2019-047

Keywordsmastitis, thioridazine (TZ), miconazole (MCZ), cloxacillin (CXN), combination therapy

© 2019 Wenjing Luan et al., published by Sciendo

This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

Keywords
mastitis, thioridazine (TZ), miconazole (MCZ), cloxacillin (CXN), combination therapy