Abstract:
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.
