| Autor: |
Mmakola K; Department of Immunology, Faculty of Health Sciences, University of Pretoria, Pretoria 0001, South Africa., Balmith M; Department of Pharmacology, Faculty of Health Sciences, University of Pretoria, Pretoria 0084, South Africa., Steel H; Department of Immunology, Faculty of Health Sciences, University of Pretoria, Pretoria 0001, South Africa., Said M; Department of Medical Microbiology, Faculty of Health Sciences, University of Pretoria, Pretoria 0001, South Africa.; Department of Medical Microbiology, Tshwane Academic Division, National Health Laboratory Services, Pretoria 0001, South Africa., Potjo M; Department of Immunology, Faculty of Health Sciences, University of Pretoria, Pretoria 0001, South Africa.; Department of Immunology, Tshwane Academic Division, National Health Laboratory Services, Pretoria 0002, South Africa., van der Mescht M; Department of Immunology, Faculty of Health Sciences, University of Pretoria, Pretoria 0001, South Africa., Hlatshwayo N; Department of Immunology, Faculty of Health Sciences, University of Pretoria, Pretoria 0001, South Africa.; Department of Immunology, Tshwane Academic Division, National Health Laboratory Services, Pretoria 0002, South Africa., Meyer P; Department of Immunology, Faculty of Health Sciences, University of Pretoria, Pretoria 0001, South Africa.; Department of Immunology, Tshwane Academic Division, National Health Laboratory Services, Pretoria 0002, South Africa., Tintinger G; Department of Internal Medicine, Steve Biko Academic Hospital, Faculty of Health Sciences, University of Pretoria, Pretoria 0002, South Africa., Anderson R; Department of Immunology, Faculty of Health Sciences, University of Pretoria, Pretoria 0001, South Africa.; Clinical and Translational Research Unit of the Rosebank, Oncology Centre, Johannesburg 2196, South Africa., Cholo M; Department of Immunology, Faculty of Health Sciences, University of Pretoria, Pretoria 0001, South Africa.; Basic and Translational Research Unit, Nuclear Medicine Research Infrastructure, Steve Biko Academic Hospital, Pretoria 0001, South Africa. |
| Abstrakt: |
Multidrug-resistant tuberculosis (MDR-TB) patients are treated with a standardised, short World Health Organization (WHO) regimen which includes clofazimine (CFZ) and bedaquiline (BDQ) antibiotics. These two antibiotics lead to the development of QT prolongation in patients, inhibiting potassium (K + ) uptake by targeting the voltage-gated K + (Kv)11.1 (hERG) channel of the cardiomyocytes (CMs). However, the involvement of these antibiotics to regulate other K + transporters of the CMs, as potential mechanisms of QT prolongation, has not been explored. This study determined the effects of CFZ and BDQ on sodium, potassium-adenosine triphosphatase (Na + ,K + -ATPase) activity of CMs using rat cardiomyocytes (RCMs). These cells were treated with varying concentrations of CFZ and BDQ individually and in combination (1.25-5 mg/L). Thereafter, Na + ,K + -ATPase activity was determined, followed by intracellular adenosine triphosphate (ATP) quantification and cellular viability determination. Furthermore, molecular docking of antibiotics with Na + ,K + -ATPase was determined. Both antibiotics demonstrated dose-response inhibition of Na + ,K + -ATPase activity of the RCMs. The greatest inhibition was demonstrated by combinations of CFZ and BDQ, followed by BDQ alone and, lastly, CFZ. Neither antibiotic, either individually or in combination, demonstrated cytotoxicity. Molecular docking revealed an interaction of both antibiotics with Na + ,K + -ATPase, with BDQ showing higher protein-binding affinity than CFZ. The inhibitory effects of CFZ and BDQ, individually and in combination, on the activity of Na + ,K + -ATPase pump of the RCMs highlight the existence of additional mechanisms of QT prolongation by these antibiotics. |
