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Journal article
Metabolic adjustments of blood-stage Plasmodium falciparum in response to sublethal pyrazoleamide exposure
Scientific reports, v 12(1), pp 1167-1167
21 Jan 2022
PMID: 35064153
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Due to the recurring loss of antimalarial drugs to resistance, there is a need for novel targets, drugs, and combination therapies to ensure the availability of current and future countermeasures. Pyrazoleamides belong to a novel class of antimalarial drugs that disrupt sodium ion homeostasis, although the exact consequences of this disruption in Plasmodium falciparum remain under investigation. In vitro experiments demonstrated that parasites carrying mutations in the metabolic enzyme PfATP4 develop resistance to pyrazoleamide compounds. However, the underlying mechanisms that allow mutant parasites to evade pyrazoleamide treatment are unclear. Here, we first performed experiments to identify the sublethal dose of a pyrazoleamide compound (PA21A092) that caused a significant reduction in growth over one intraerythrocytic developmental cycle (IDC). At this drug concentration, we collected transcriptomic and metabolomic data at multiple time points during the IDC to quantify gene- and metabolite-level alterations in the treated parasites. To probe the effects of pyrazoleamide treatment on parasite metabolism, we coupled the time-resolved omics data with a metabolic network model of P. falciparum. We found that the drug-treated parasites adjusted carbohydrate metabolism to enhance synthesis of myoinositol-a precursor for phosphatidylinositol biosynthesis. This metabolic adaptation caused a decrease in metabolite flux through the pentose phosphate pathway, causing a decreased rate of RNA synthesis and an increase in oxidative stress. Our model analyses suggest that downstream consequences of enhanced myoinositol synthesis may underlie adjustments that could lead to resistance emergence in P. falciparum exposed to a sublethal dose of a pyrazoleamide drug.
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Details
- Title
- Metabolic adjustments of blood-stage Plasmodium falciparum in response to sublethal pyrazoleamide exposure
- Creators
- Shivendra G Tewari - Henry M. Jackson FoundationBobby Kwan - Johns Hopkins UniversityRubayet Elahi - Johns Hopkins UniversityKrithika Rajaram - Johns Hopkins UniversityJaques Reifman - United States Army Medical CommandSean T Prigge - Johns Hopkins UniversityAkhil B Vaidya - Drexel UniversityAnders Wallqvist - United States Army Medical Command
- Publication Details
- Scientific reports, v 12(1), pp 1167-1167
- Publisher
- Springer Nature
- Grant note
- W81XWH-14-2-0134 / U.S. Army Medical Research and Development Command (MRDC) R01 AI132508 / NIAID NIH HHS W81XWH-20-C-0031 / U.S. Army Medical Research and Development Command (MRDC) R01 AI098413 / NIAID NIH HHS W81XWH-15-C-0061 / U.S. Army Medical Research and Development Command (MRDC) T32 AI007417 / NIAID NIH HHS R01AI125534 / Division of Intramural Research, National Institute of Allergy and Infectious Diseases (Division of Intramural Research of the NIAID)
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Microbiology and Immunology
- Web of Science ID
- WOS:000746132400023
- Scopus ID
- 2-s2.0-85123474356
- Other Identifier
- 991019168063404721
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- Collaboration types
- Industry collaboration
- Domestic collaboration
- Web of Science research areas
- Biochemistry & Molecular Biology