Artemisinin-resistant K13 mutations rewire Plasmodium falciparum's intra-erythrocytic metabolic program to enhance survival

Mok, S. et al. (2021) Artemisinin-resistant K13 mutations rewire Plasmodium falciparum's intra-erythrocytic metabolic program to enhance survival. Nature Communications, 12, 530. (doi: 10.1038/s41467-020-20805-w) (PMID:33483501) (PMCID:PMC7822823)

Abstract

The emergence and spread of artemisinin resistance, driven by mutations in Plasmodium falciparum K13, has compromised antimalarial efficacy and threatens the global malaria elimination campaign. By applying systems-based quantitative transcriptomics, proteomics, and metabolomics to a panel of isogenic K13 mutant or wild-type P. falciparum lines, we provide evidence that K13 mutations alter multiple aspects of the parasite's intra-erythrocytic developmental program. These changes impact cell-cycle periodicity, the unfolded protein response, protein degradation, vesicular trafficking, and mitochondrial metabolism. K13-mediated artemisinin resistance in the Cambodian Cam3.II line was reversed by atovaquone, a mitochondrial electron transport chain inhibitor. These results suggest that mitochondrial processes including damage sensing and anti-oxidant properties might augment the ability of mutant K13 to protect P. falciparum against artemisinin action by helping these parasites undergo temporary quiescence and accelerated growth recovery post drug elimination.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Stokes, Ms Barbara and Tobin, Andrew
• Authors: Mok, S., Stokes, B. H., Gnädig, N. F., Ross, L. S., Yeo, T., Amaratunga, C., Allman, E., Solyakov, L., Bottrill, A. R., Tripathi, J., Fairhurst, R. M., Llinás, M., Bozdech, Z., Tobin, A. B., and Fidock, D. A.
• College/School: College of Medical Veterinary and Life Sciences > School of Molecular Biosciences; College of Medical Veterinary and Life Sciences > School of Infection & Immunity
• Journal Name: Nature Communications
• Publisher: Nature Research
• ISSN: 2041-1723
• ISSN (Online): 2041-1723
• Copyright Holders: Copyright © 2021 The Authors
• First Published: First published in Nature Communications 12: 530
• Publisher Policy: Reproduced under a Creative Commons License