Ouji Manel, Reyser Thibaud, Yamaryo-Botté Yoshiki, Nguyen Michel, Rengel David, Dutreuil Axelle, Marcellin Marlène, Burlet-Schiltz Odile, Augereau Jean-Michel, Riscoe Michael K, Paloque Lucie, Botté Cyrille, Benoit-Vical Françoise
LCC-CNRS, Laboratoire de Chimie de Coordination, Université de Toulouse, CNRS, Toulouse, France; MAAP, New Antimalarial Molecules and Pharmacological Approaches, Inserm ERL 1289, Toulouse, France; Institut de Pharmacologie et de Biologie Structurale (IPBS), Université de Toulouse, CNRS, Université Toulouse III - Paul Sabatier (UT3), Toulouse, France.
ApicoLipid Team, Institute for Advanced Biosciences, CNRS UMR5309, Université Grenoble Alpes, INSERM U1209, Grenoble, France.
Int J Parasitol Drugs Drug Resist. 2024 Dec;26:100565. doi: 10.1016/j.ijpddr.2024.100565. Epub 2024 Sep 19.
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.
疟原虫对一线抗疟疗法青蒿素产生耐药性并传播，这对疟疾根除政策构成威胁。为了确定消除青蒿素耐药性疟原虫的治疗靶点，研究了顶质体和线粒体的功能，重点关注顶质体中的II型脂肪酸合成（FASII）途径和线粒体中的电子传递链。在双氢青蒿素治疗下，青蒿素耐药性疟原虫上调基因中FASII途径显著富集，这与已发表的转录组数据一致。然而，通过对脂肪酸的气相色谱-质谱分析，我们首次证明FASII途径无功能，排除了使用FASII抑制剂靶向青蒿素耐药性疟原虫的可能性。相反，通过评估氧消耗率的调节，我们证明线粒体呼吸在青蒿素耐药性疟原虫中甚至在静止期仍保持功能且具有灵活性。两种靶向电子传递链的新型化合物（ELQ300、ELQ400）能有效杀死静止期的青蒿素耐药性疟原虫。因此，线粒体呼吸是消除青蒿素耐药性持续性恶性疟原虫的关键靶点。
