Rapid kill of malaria parasites by artemisinin and semi-synthetic endoperoxides involves ROS-dependent depolarization of the membrane potential

Antoine, Thomas, Fisher, Nicholas, Amewu, R., O'Neill, P. M., Ward, Stephen ORCID: https://orcid.org/0000-0003-2331-3192 and Biagini, Giancarlo ORCID: https://orcid.org/0000-0001-6356-6595 (2014) 'Rapid kill of malaria parasites by artemisinin and semi-synthetic endoperoxides involves ROS-dependent depolarization of the membrane potential'. Journal of Antimicrobial Chemotherapy, Vol 69, Issue 4, pp. 1005-1016.

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Abstract

Objectives Artemisinin 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.

Methods Parasite 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.

Results Parasite 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.

Conclusions The 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.

Item Type:	Article
Subjects:	QU Biochemistry > Cells and Genetics > QU 350 Cellular structures QV Pharmacology > Anti-Inflammatory Agents. Anti-Infective Agents. Antineoplastic Agents > QV 256 Antimalarials QX Parasitology > Protozoa > QX 135 Plasmodia WA Public Health > Preventive Medicine > WA 110 Prevention and control of communicable diseases. Transmission of infectious diseases WC Communicable Diseases > Tropical and Parasitic Diseases > WC 750 Malaria
Faculty: Department:	Biological Sciences > Department of Tropical Disease Biology
Digital Object Identifer (DOI):	https://doi.org/10.1093/jac/dkt486
Depositing User:	Lynn Roberts-Maloney
Date Deposited:	25 Apr 2014 12:14
Last Modified:	06 Feb 2018 13:07
URI:	https://archive.lstmed.ac.uk/id/eprint/3681

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