title: Fatty acid synthesis and pyruvate metabolism pathways remain active in dihydroartemisinin-induced dormant ring stages of Plasmodium falciparum.
abstract: Artemisinin (ART)-based combination therapy (ACT) is used as the first-line treatment of uncomplicated falciparum malaria worldwide. However, despite high potency and rapid action, there is a high rate of recrudescence associated with ART monotherapy or ACT long before the recent emergence of ART resistance. ART-induced ring-stage dormancy and recovery have been implicated as possible causes of recrudescence; however, little is known about the characteristics of dormant parasites, including whether dormant parasites are metabolically active. We investigated the transcription of 12 genes encoding key enzymes in various metabolic pathways in P. falciparum during dihydroartemisinin (DHA)-induced dormancy and recovery. Transcription analysis showed an immediate downregulation for 10 genes following exposure to DHA but continued transcription of 2 genes encoding apicoplast and mitochondrial proteins. Transcription of several additional genes encoding apicoplast and mitochondrial proteins, particularly of genes encoding enzymes in pyruvate metabolism and fatty acid synthesis pathways, was also maintained. Additions of inhibitors for biotin acetyl-coenzyme A (CoA) carboxylase and enoyl-acyl carrier reductase of the fatty acid synthesis pathways delayed the recovery of dormant parasites by 6 and 4 days, respectively, following DHA treatment. Our results demonstrate that most metabolic pathways are downregulated in DHA-induced dormant parasites. In contrast, fatty acid and pyruvate metabolic pathways remain active. These findings highlight new targets to interrupt recovery of parasites from ART-induced dormancy and to reduce the rate of recrudescence following ART treatment.
authors.affiliation: Drug Resistance and Diagnostics, Australian Army Malaria Institute, Brisbane, Australia.
authors.forename: Nanhua
authors.initials: N
authors.lastname: Chen
authors.affiliation: Department of Global Health, University of South Florida, Tampa, Florida, USA.
authors.forename: Alexis N
authors.initials: AN
authors.lastname: LaCrue
authors.affiliation: Drug Resistance and Diagnostics, Australian Army Malaria Institute, Brisbane, Australia Malaria Drug Resistance and Chemotherapy, Queensland Institute of Medical Research, Brisbane, Australia.
authors.forename: Franka
authors.initials: F
authors.lastname: Teuscher
authors.affiliation: Experimental Therapeutics, Walter Reed Army Institute of Research, Silver Spring, Maryland, USA.
authors.forename: Norman C
authors.initials: NC
authors.lastname: Waters
authors.affiliation: Malaria Drug Resistance and Chemotherapy, Queensland Institute of Medical Research, Brisbane, Australia School of Public Health & Social Work, Queensland University of Technology, Brisbane, Australia.
authors.forename: Michelle L
authors.initials: ML
authors.lastname: Gatton
authors.affiliation: Department of Global Health, University of South Florida, Tampa, Florida, USA.
authors.forename: Dennis E
authors.initials: DE
authors.lastname: Kyle
authors.affiliation: Drug Resistance and Diagnostics, Australian Army Malaria Institute, Brisbane, Australia Malaria Drug Resistance and Chemotherapy, Queensland Institute of Medical Research, Brisbane, Australia qin.cheng@defence.gov.au.
authors.forename: Qin
authors.initials: Q
authors.lastname: Cheng
mesh_terms: D000103:Acetyl-CoA Carboxylase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000962:Antimalarials / Q000494:pharmacology; D063546:Apicoplasts / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D037621:Artemisinins / Q000494:pharmacology; D050753:Enoyl-(Acyl-Carrier-Protein) Reductase (NADH) / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004912:Erythrocytes / Q000187:drug effects / Q000469:parasitology; D005227:Fatty Acids / Q000096:biosynthesis*; D005786:Gene Expression Regulation; D006801:Humans; D008018:Life Cycle Stages / Q000187:drug effects / Q000235:genetics*; D053858:Metabolic Networks and Pathways / Q000187:drug effects / Q000235:genetics; D008928:Mitochondria / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D010963:Plasmodium falciparum / Q000187:drug effects / Q000235:genetics / Q000254:growth & development / Q000378:metabolism*; D015800:Protozoan Proteins / Q000235:genetics / Q000378:metabolism*; D011773:Pyruvates / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D004791:Enzyme Inhibitors; D005227:Fatty Acids; D024101:Mitochondrial Proteins; D015800:Protozoan Proteins; D011773:Pyruvates; C039060:artenimol; C031327:artemisinin; D050753:Enoyl-(Acyl-Carrier-Protein) Reductase (NADH); D000103:Acetyl-CoA Carboxylase