Fatty acid synthesis and pyruvate metabolism pathways remain active in dihydroartemisinin induced dormant ring stages of Plasmodium falciparum

Chen, Nanhua, LaCrue, Alexis N., Teuscher, Franka, Waters, Norman C., Gatton, Michelle L., Kyle, Dennis E., & Cheng, Qin (2014) Fatty acid synthesis and pyruvate metabolism pathways remain active in dihydroartemisinin induced dormant ring stages of Plasmodium falciparum. Antimicrobial Agents and Chemotherapy, 58(8), pp. 4773-4781.

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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 has been implicated as possible cause 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 down regulation 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 genes encoding enzymes in pyruvate metabolism and fatty acid synthesis pathways, were also maintained. Additions of inhibitors for biotin acetyl CoA carbozylase 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 most metabolic pathways are down regulated 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.

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ID Code: 72551
Item Type: Journal Article
Refereed: Yes
Additional URLs:
Keywords: Plasmodium falciparum, artemisinin, dormant, metabolic activity, gene expression, pyruvate metabolism, fatty acid synthesis
DOI: 10.1128/AAC.02647-14
ISSN: 1070-6283
Subjects: Australian and New Zealand Standard Research Classification > BIOLOGICAL SCIENCES (060000) > BIOCHEMISTRY AND CELL BIOLOGY (060100) > Cell Metabolism (060104)
Australian and New Zealand Standard Research Classification > BIOLOGICAL SCIENCES (060000) > GENETICS (060400) > Gene Expression (incl. Microarray and other genome-wide approaches) (060405)
Australian and New Zealand Standard Research Classification > MEDICAL AND HEALTH SCIENCES (110000) > MEDICAL MICROBIOLOGY (110800) > Medical Parasitology (110803)
Divisions: Current > QUT Faculties and Divisions > Faculty of Health
Current > Schools > School of Public Health & Social Work
Funding:
Copyright Owner: Copyright 2014 American Society for Microbiology
Deposited On: 30 Jun 2014 22:32
Last Modified: 07 Aug 2014 22:54

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