Abstract
ObjectivesArtemisinin and artemisinin semi-synthetic derivatives (collectively known as endoperoxides) are first-line antimalarials for the treatment of uncomplicated and severe malaria. Endoperoxides display very fast killing rates and are generally recalcitrant to parasite resistance development. These key pharmacodynamic features are a result of a complex mechanism of action, the details of which lack consensus. Here, we report on the primary physiological events leading to parasite death.MethodsParasite mitochondrial (ΔΨm) and plasma membrane (ΔΨp) electrochemical potentials were measured using real-time single-cell imaging following exposure to pharmacologically relevant concentrations of endoperoxides (artemisinin, dihydroartemisinin, artesunate and the synthetic tetraoxane RKA182). In addition, mitochondrial electron transport chain components NADH:quinone oxidoreductase (alternative complex I), bc1 (complex III) and cytochrome oxidase (complex IV) were investigated to determine their functional sensitivity to the various endoperoxides.ResultsParasite exposure to endoperoxides resulted in rapid depolarization of parasite ΔΨm and ΔΨp. The rate of depolarization was decreased in the presence of a reactive oxygen species (ROS) scavenger and Fe3+ chelators. Depolarization of ΔΨm by endoperoxides is not believed to be through the inhibition of mitochondrial electron transport chain components, owing to the lack of significant inhibition when assayed directly.ConclusionsThe depolarization of ΔΨm and ΔΨp is shown to be mediated via the generation of ROS that are initiated by iron bioactivation of endoperoxides and/or catalysed by iron-dependent oxidative stress. These data are discussed in the context of current hypotheses concerning the mode of action of endoperoxides.
Highlights
Artemisinin is a tetracyclic 1,2,4-trioxane containing an endoperoxide bridge (C-O-O-C; Figure 1), the key pharmacophore of the drug.[1]
We have previously described the use of a real-time single-cell imaging method for monitoring malaria parasite mitochondrial (DCm) and plasma membrane potential (DCp)[43,44] and reported malaria parasite electron transport chain (ETC) activities including PfNDH2.40,45 Using these approaches, we have re-examined the effect of endoperoxides on parasite bioenergetic functions and discuss our data in the context of the current hypotheses
There is conflicting evidence on the role of the parasite ETC in the activation and/or resultant mitochondrial dysfunction following the exposure of parasites to endoperoxides
Summary
Artemisinin is a tetracyclic 1,2,4-trioxane containing an endoperoxide bridge (C-O-O-C; Figure 1), the key pharmacophore of the drug.[1] To improve the solubility and pharmacological activity of artemisinin, a first series of semi-synthetic compounds were synthesized with a similar backbone but with modifications at the C10 position, generating hemi-acetal, ether or ester derivatives such as dihydroartemisinin, artemether and artesunate (Figure 1). Located in the core of the structure, its cleavage generates short-lived cytotoxic oxyradicals in the presence of haem iron or free iron Fe2+.5,6. From this premise of ‘endoperoxide bioactivation’, two different mechanisms have been proposed. The first, proposed by the Posner laboratory using 18O-labelled trioxane analogues, hypothesizes that the oxygen-centred radicals produced are rearranged to more stable carbon-centred radicals.[7,8] In this ‘reductive
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