Abstract:
Although bedaquiline has advanced the treatment of multidrug-resistant tuberculosis (TB),
concerns remain about the cardiotoxic potential of this agent, albeit by unexplored
mechanisms. Accordingly, we have investigated augmentation of the reactivity of
human platelets in vitro as a potential mechanism of bedaquiline-mediated
cardiotoxicity. Platelet-rich plasma (PRP) or isolated cells prepared from the blood of
healthy, adult humans were treated with bedaquiline (0.625–10 μg/ml), followed by
activation with adenosine 5’-diphosphate (ADP), thrombin or the thromboxane A2
receptor agonist (U46619). Expression of platelet CD62P (P-selectin), platelet
aggregation, Ca2+ fluxes and phosphorylation of Akt1 were measured using flow
cytometry, spectrophotometry, fluorescence spectrometry, and by ELISA procedures,
respectively. Exposure to bedaquiline caused dose-related inhibition of ADP-activated,
but not thrombin- or U46619-activated, expression of CD62P by platelets, achieving
statistical significance at a threshold concentration of 5 μg/ml and was paralleled by
inhibition of aggregation and Ca2+ mobilization. These ADP-selective inhibitory effects of
bedaquiline on platelet activation were mimicked by wortmannin, an inhibitor
of phosphatidylinositol 3-kinase (PI3-K), implicating PI3-K as being a common target of
both agents, a contention that was confirmed by the observed inhibitory effects of
bedaquiline on the phosphorylation of Akt1 following activation of platelets with ADP.
These apparent inhibitory effects of bedaquiline on the activity of PI3-K may result from the secondary cationic amphiphilic properties of this agent. If operative in vivo, these anti-platelet
effects of bedaquiline may contribute to ameliorating the risk of TB-associated cardiovascular
disease, but this remains to be explored in the clinical setting.
