Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Sodium, Potassium Adenosine Triphosphatase as a Potential Target of the Anti-Tuberculosis Agents, Clofazimine and Bedaquiline

Khomotso Mmakola
ORCID logo ,
Helen Steel
ORCID logo ,
Mohamed Said
,
Moliehi Potjo
,
Mieke van der Mescht
,
Nomsa Hlatshwayo
,
Pieter Meyer
ORCID logo ,
Gregory Tintinger
,
Ronald Anderson
ORCID logo ,
Moloko Cholo
*
Version 1 : Received: 17 September 2024 / Approved: 18 September 2024 / Online: 18 September 2024 (13:05:29 CEST)

How to cite: Mmakola, K.; Steel, H.; Said, M.; Potjo, M.; van der Mescht, M.; Hlatshwayo, N.; Meyer, P.; Tintinger, G.; Anderson, R.; Cholo, M. Sodium, Potassium Adenosine Triphosphatase as a Potential Target of the Anti-Tuberculosis Agents, Clofazimine and Bedaquiline. Preprints 2024, 2024091413. https://doi.org/10.20944/preprints202409.1413.v1 Mmakola, K.; Steel, H.; Said, M.; Potjo, M.; van der Mescht, M.; Hlatshwayo, N.; Meyer, P.; Tintinger, G.; Anderson, R.; Cholo, M. Sodium, Potassium Adenosine Triphosphatase as a Potential Target of the Anti-Tuberculosis Agents, Clofazimine and Bedaquiline. Preprints 2024, 2024091413. https://doi.org/10.20944/preprints202409.1413.v1

Abstract

Multidrug-resistant-tuberculosis (MDR-TB) patients are treated with a standardised, short, WHO-regimen, which includes clofazimine (CFZ) and bedaquiline (BDQ) antibiotics. These two antibiotics lead to development of QT prolongation in patients, inhibiting potassium (K+) uptake by targeting the Kv11.1 (hERG) channel of the cardiomyocytes (CMs). However, the involvement of these antibiotics on 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 the sodium, potassium-adenosine triphosphatase (Na+,K+-ATPase) activity of CMs, using the 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. Both antibiotics demonstrated dose-response inhibition of the 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, individually or in combination, demonstrated cytotoxicity under the experimental conditions used. The inhibitory effects of CFZ and BDQ individually and in combination, on the activity of the Na+,K+-ATPase pump of the RCMs highlight the existence of additional mechanisms of QT prolongation by these antibiotics.

Keywords

Bedaquiline; clofazimine; cardiomyocytes; cellular viability; multidrug-resistant-tuberculosis; sodium, potassium-adenosine triphosphatase; adenosine triphosphate

Subject

Medicine and Pharmacology, Cardiac and Cardiovascular Systems

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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