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Metabolic Adjustments of Blood-Stage Plasmodium falciparum in Response to Sublethal Pyrazoleamide Exposure

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 an approximately 50% 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.

ORGANISM(S): Plasmodium falciparum

PROVIDER: GSE176469 | GEO | 2022/01/21

REPOSITORIES: GEO

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Project description:Spiroindolone and pyrazoleamide antimalarial compounds target Plasmodium falciparum P-type ATPase (PfATP4) and induce disruption of intra-cellular Na+ homeostasis. Recently, a PfATP4 mutation was discovered that confers resistance to a pyrazoleamide while increasing sensitivity to a spiroindolone. To understand the different cellular accommodation to PfATP4 disruptions, we examined biochemical and metabolic adaptations that underlie this seemingly contradictory response of P. falciparum to sublethal concentrations of each compound. We used a genetically engineered P. falciparum Dd2 strain (Dd2A211V) carrying an Ala211Val (A211V) mutation in PfATP4 to identify metabolic adaptations associated with the mutation that results in decreased sensitivity to PA21A092 (a pyrazoleamide) and increased sensitivity of KAE609 (a spiroindolone). We first identified sublethal doses of PA21A092 and KAE609 causing substantial reduction (30-70%) in Dd2A211V parasite replication. At this sublethal dose of PA21A092 (or KAE609), we collected metabolomic and transcriptomic data during the first intraerythrocytic developmental cycle (IDC). Finally, we integrated the time-resolved data with a whole-genome metabolic network model of P. falciparum to characterize antimalarial-induced physiological adaptations. We found that sublethal treatment with PA21A092 caused significant (p < 0.001) alterations in the abundances of 91 Plasmodium gene transcripts whereas only 21 transcripts were significantly altered due to sublethal treatment with KAE609. In the metabolomic data, we found a substantial alteration (fourfold) in the abundances of carbohydrate metabolites in the presence of either compounds. The estimated rates of macromolecule syntheses between the two antimalarial-treated conditions were also comparable, except for the rate of lipid synthesis. A closer examination of parasite metabolism in the presence of either compound indicated statistically significant differences in enzymatic activities associated with synthesis of phosphatidylcholine, phosphatidylserine, and phosphatidylinositol. Our results suggest that malaria parasites activate protein kinases via phospholipid-dependent signaling in response to the ionic perturbation induced by the Na+ homeostasis disruptor PA21A092. Therefore, we hypothesize that targeted disruption of phospholipid signaling in PA21A092-resistant parasites could be a means to block the emergence of resistance to PA21A092.

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Metabolic Adjustments of Blood-Stage Plasmodium falciparum in Response to Sublethal Pyrazoleamide Exposure

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