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PROVIDER: PRJNA1230203 | ENA |
REPOSITORIES: ENA
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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.
2023-02-14 | GSE218998 | GEO
Project description:Transcription time course of Plasmodium falciparum parasite asexual blood stage progression in the presence of antimalarial drug CID5750730 (Compound C)
2022-05-13 | GSE202876 | GEO
Project description:Genomic analysis of P falciparum strains with a mutation in the Plasmodium falciparum Na+ pump PfATP4
| PRJEB53576 | ENA
Project description:<p>Characterizing the mode of action of antimalarial compounds that emerge from high-throughput phenotypic screens is central to understanding how parasite resistance to these drugs can emerge. Here, we have employed untargeted metabolomics to inform on the mechanism of action of antimalarial leads with different speed of kill profiles being developed by the Novartis Institute of Tropical Diseases (NITD). Time-resolved global changes in malaria parasite metabolite profiles upon drug treatment were quantified using liquid chromatography-based mass spectrometry (LC-MS) and compared to untreated controls. Using this approach, we confirmed previously reported metabolomics profiles of the fast-killing (2.5 h) drug dihydroartemisinin (DHA) and the slower killing atovaquone (ATQ). A slow acting antimalarial lead from NITD of imidazolopiperazine (IZP) class, GNF179, elicited little or no discernable metabolic change in malaria parasites in the same 2.5 h window of drug exposure. In contrast, fast killing drugs, DHA and the spiroindolone (NITD246) elicited similar metabolomic profiles both in terms of kinetics and content. DHA and NITD246 induced peptide losses consistent with disruption of haemoglobin catabolism and also interfered with the pyrimidine biosynthesis pathway. Two members of the recently described novel class of antimalarial agents of the 5-aryl-2-amino-imidazothiadiazole (ITD) class also exhibited a fast-acting profile that also featured peptide losses indicative of disrupted haemoglobin catabolism. Our screen demonstrates that structurally unrelated, fast acting antimalarial compounds generate similar biochemical signatures in <em>Plasmodium</em> pointing to a common mechanism associated with rapid parasite death. These profiles may be used to identify and possibly predict the mode of action of other fast-acting drug candidates.</p>
2023-09-27 | MTBLS6580 | MetaboLights
Project description:A G358S mutation in the Plasmodium falciparum Na+ pump PfATP4 confers clinically relevant levels of resistance to cipargamin
| PRJEB55457 | ENA
Project description:The increasing spread of drug-resistant malaria strains underscores the need for new antimalarial agents with novel modes of action (MOAs). Here, we describe a compound representative of a new class of antimalarials. This molecule, ACT-213615, potently inhibits in vitro erythrocytic growth of all tested Plasmodium falciparum strains, irrespective of their drug resistance properties, with IC(50) values in the low single-digit nanomolar range. Like the clinically used artemisinins, the compound equally and very rapidly affects all three asexual erythrocytic parasite stages. In contrast, microarray studies suggest that the MOA of ACT-213615 is different from that of the artemisinins and other known antimalarials. ACT-213615 is orally bioavailable in mice, exhibits activity in the murine P. berghei model and efficacy comparable to that of the reference drug chloroquine in the recently established P. falciparum SCID mouse model.ACT-213615 represents a new class of potent antimalarials that merits further investigation for its clinical potential. Histone deacetylase (HDACs) inhibitors are being intensively pursued as potential new antimalarial drugs, and are also emerging as valuable tools for investigating transcriptional control in malaria parasites. In this study, the genome-wide transcriptional effects of three structurally related hydroxamate HDAC inhibitors were profiled in Plasmodium falciparum, the most lethal of the malaria parasite species that infects humans. Trophozoite-stage P. falciparum cells were treated with ACT-213615 for increasing amount of time at IC50 concentration and cells were harvested in parralled with DMSO treated controls for microarray-based transcriptional profiling.
2012-07-19 | E-GEOD-39485 | biostudies-arrayexpress
Project description: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.
2022-01-21 | GSE176469 | GEO
Project description:The increasing spread of drug-resistant malaria strains underscores the need for new antimalarial agents with novel modes of action (MOAs). Here, we describe a compound representative of a new class of antimalarials. This molecule, ACT-213615, potently inhibits in vitro erythrocytic growth of all tested Plasmodium falciparum strains, irrespective of their drug resistance properties, with IC(50) values in the low single-digit nanomolar range. Like the clinically used artemisinins, the compound equally and very rapidly affects all three asexual erythrocytic parasite stages. In contrast, microarray studies suggest that the MOA of ACT-213615 is different from that of the artemisinins and other known antimalarials. ACT-213615 is orally bioavailable in mice, exhibits activity in the murine P. berghei model and efficacy comparable to that of the reference drug chloroquine in the recently established P. falciparum SCID mouse model.ACT-213615 represents a new class of potent antimalarials that merits further investigation for its clinical potential. Histone deacetylase (HDACs) inhibitors are being intensively pursued as potential new antimalarial drugs, and are also emerging as valuable tools for investigating transcriptional control in malaria parasites. In this study, the genome-wide transcriptional effects of three structurally related hydroxamate HDAC inhibitors were profiled in Plasmodium falciparum, the most lethal of the malaria parasite species that infects humans.
2012-07-20 | GSE39485 | GEO
Project description:We examined adaptive morphological divergence and epigenetic variation in genetically impoverished asexual populations of a freshwater snail, Potamopyrgus antipodarum from distinct environments. These populations exhibit environment-specific adaptive divergence in shell shape and significant genome wide DNA methylation differences among differentially adapted lake and fast water flow river populations. The epigenetic variation correlated with adaptive phenotypic variation in rapidly adapting asexual animal populations. This provides one of the first examples of environmentally-driven differences in epigenetics that associates with adaptive phenotypic divergence.
2017-08-18 | GSE93836 | GEO
Project description:We examined adaptive morphological divergence and epigenetic variation in genetically impoverished asexual populations of a freshwater snail, Potamopyrgus antipodarum from distinct environments. These populations exhibit environment-specific adaptive divergence in shell shape and significant genome wide DNA methylation differences among differentially adapted lake and fast water flow river populations. The epigenetic variation correlated with adaptive phenotypic variation in rapidly adapting asexual animal populations. This provides one of the first examples of environmentally-driven differences in epigenetics that associates with adaptive phenotypic divergence.
2017-08-18 | GSE99911 | GEO