In artemisinin-resistant falciparum malaria parasites, mitochondrial metabolic pathways are essential for survival but not those of apicoplast
Emergence and spread of parasite resistance to artemisinins, the first-line antimalarial therapy, threaten the malaria eradication policy. To identify therapeutic targets to eliminate artemisinin-resistant parasites, the functioning of the apicoplast and the mitochondrion was studied, focusing on the fatty acid synthesis type II (FASII) pathway in the apicoplast and the electron transfer chain in the mitochondrion. A significant enrichment of the FASII pathway among the up-regulated genes in artemisinin-resistant parasites under dihydroartemisinin treatment was found, in agreement with published transcriptomic data. However, using GC-MS analyzes of fatty acids, we demonstrated for the first time that the FASII pathway is non-functional, ruling out the use of FASII inhibitors to target artemisinin-resistant parasites. Conversely, by assessing the modulation of the oxygen consumption rate, we evidenced that mitochondrial respiration remains functional and flexible in artemisinin-resistant parasites and even at the quiescent stage. Two novel compounds targeting electron transport chain (ELQ300, ELQ400) efficiently killed quiescent artemisinin-resistant parasites. Therefore, mitochondrial respiration represents a key target for the elimination of artemisinin-resistant persistent Plasmodium falciparum parasites.
Authors
- Françoise Benoit‐Vical (ORCID: https://orcid.org/0000-0002-9468-4823)
- Michael K. Riscoe (ORCID: https://orcid.org/0000-0002-1343-5279)
- David Rengel (ORCID: https://orcid.org/0000-0003-0054-1598)
- Cyrille Y. Botté (ORCID: https://orcid.org/0000-0002-2245-536X)
- Manel Ouji
- Marlène Marcellin (ORCID: https://orcid.org/0000-0001-7683-5897)
- Jean‐Michel Augereau (ORCID: https://orcid.org/0000-0002-2847-1969)
- Michel Nguyen (ORCID: https://orcid.org/0000-0002-6496-0495)
- Odile Burlet‐Schiltz (ORCID: https://orcid.org/0000-0002-3606-2356)
- Thibaud Reyser
- Lucie Paloque (ORCID: https://orcid.org/0000-0003-0359-3959)
- Yoshiki Yamaryo‐Botté (ORCID: https://orcid.org/0000-0002-9349-4411)
- Axelle Dutreuil
Institutions
- Centre National de la Recherche Scientifique (FR)
- Université Toulouse III - Paul Sabatier (FR)
- Inserm (FR)
- Oregon Health & Science University (US)
- Université Fédérale de Toulouse Midi-Pyrénées (FR)
- Commissariat à l'Énergie Atomique et aux Énergies Alternatives (FR)
- Institut de Recherche Interdisciplinaire de Grenoble (FR)
- Institut de Pharmacologie et de Biologie Structurale (FR)
- Laboratoire de Chimie de Coordination (FR)
- VA Portland Health Care System (US)
- Institut de Biosciences et Biotechnologies (FR)
- Institut pour l'avancée des biosciences (FR)
- Université Grenoble Alpes (FR)
Publication Details
- Journal
- International Journal for Parasitology Drugs and Drug Resistance
- Published
- 2024-09-19
- DOI
- https://doi.org/10.1016/j.ijpddr.2024.100565
- Citations
- 3
- Primary Topic
- Malaria Research and Control
- Type
- article
- Field-Weighted Citation Impact
- 1.63
Funders
- Sanofi
- Ministère de l'Enseignement supérieur, de la Recherche et de l'Innovation
- Université Grenoble Alpes
- Alliance Française contre les Maladies Parasitaires
- Department of Biotechnology, Ministry of Science and Technology, India
- Agence Nationale de la Recherche
- Institut National de la Santé et de la Recherche Médicale
- Indo-French Centre for the Promotion of Advanced Research
- Fondation pour la Recherche Médicale
- Centre National de la Recherche Scientifique
- Université Toulouse III - Paul Sabatier
- Sanofi Pasteur