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| Status |
Public on Feb 14, 2023 |
| Title |
Metabolic responses in blood-stage malaria parasites associated with increased and decreased sensitivity to PfATP4 inhibitors |
| Organism |
Plasmodium falciparum |
| Experiment type |
Expression profiling by array
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| Summary |
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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| Overall design |
PfDd2-A211V parasites were cultured, in quadruplicate, for 48 hours in the presence of sublethal doses of KAE609 (cipargamin drug) and PA21A092 (a pyrazoleamide compound). We collected samples every eight hours for transcriptomic profiling. The samples associated with timepoint 8 (Rep 2) of KAE609 cultures, and timepoint 32 and 40 (Rep 3) of PA21A092 cultures were lost during the hybridization process.
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| Web link |
https://malariajournal.biomedcentral.com/articles/10.1186/s12936-023-04481-x
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| Contributor(s) |
Tewari SG, Elahi R, Kwan B, Rajaram K, Bhatnagar S, Dziedzic A, Jedlicka AE, Reifman J, Prigge ST, Vaidya AB, Wallqvist A |
| Citation(s) |
36788578 |
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| Submission date |
Nov 29, 2022 |
| Last update date |
Jun 01, 2023 |
| Contact name |
Shivendra G Tewari |
| E-mail(s) |
stewari@bhsai.org
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| Phone |
3016191942
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| Organization name |
Biotechnology HPC Software Applications Institute
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| Street address |
2405 Whittier Drive, Suite 200
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| City |
Frederick |
| State/province |
MD |
| ZIP/Postal code |
21702 |
| Country |
USA |
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| Platforms (1) |
| GPL27130 |
Agilent-037237 P.falciparum_Pf3D7v7.1_Transcriptome_apimito (ORF version) |
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| Samples (53)
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| GSM6762150 |
KAE609, Time 24h, Rep 1 |
| GSM6762151 |
KAE609, Time 32h, Rep 1 |
| GSM6762152 |
KAE609, Time 40h, Rep 1 |
| GSM6762153 |
KAE609, Time 48h, Rep 1 |
| GSM6762154 |
KAE609, Time 0h, Rep 2 |
| GSM6762155 |
KAE609, Time 16h, Rep 2 |
| GSM6762156 |
KAE609, Time 24h, Rep 2 |
| GSM6762157 |
KAE609, Time 32h, Rep 2 |
| GSM6762158 |
KAE609, Time 40h, Rep 2 |
| GSM6762159 |
KAE609, Time 48h, Rep 2 |
| GSM6762160 |
KAE609, Time 0h, Rep 3 |
| GSM6762161 |
KAE609, Time 8h, Rep 3 |
| GSM6762162 |
KAE609, Time 16h, Rep 3 |
| GSM6762163 |
KAE609, Time 24h, Rep 3 |
| GSM6762164 |
KAE609, Time 32h, Rep 3 |
| GSM6762165 |
KAE609, Time 40h, Rep 3 |
| GSM6762166 |
KAE609, Time 48h, Rep 3 |
| GSM6762167 |
KAE609, Time 0h, Rep 4 |
| GSM6762168 |
KAE609, Time 8h, Rep 4 |
| GSM6762169 |
KAE609, Time 16h, Rep 4 |
| GSM6762170 |
KAE609, Time 24h, Rep 4 |
| GSM6762171 |
KAE609, Time 32h, Rep 4 |
| GSM6762172 |
KAE609, Time 40h, Rep 4 |
| GSM6762173 |
KAE609, Time 48h, Rep 4 |
| GSM6762174 |
PA21A092, Time 0h, Rep 1 |
| GSM6762175 |
PA21A092, Time 8h, Rep 1 |
| GSM6762176 |
PA21A092, Time 16h, Rep 1 |
| GSM6762177 |
PA21A092, Time 24h, Rep 1 |
| GSM6762178 |
PA21A092, Time 32h, Rep 1 |
| GSM6762179 |
PA21A092, Time 40h, Rep 1 |
| GSM6762180 |
PA21A092, Time 48h, Rep 1 |
| GSM6762181 |
PA21A092, Time 0h, Rep 2 |
| GSM6762182 |
PA21A092, Time 8h, Rep 2 |
| GSM6762183 |
PA21A092, Time 16h, Rep 2 |
| GSM6762184 |
PA21A092, Time 24h, Rep 2 |
| GSM6762185 |
PA21A092, Time 32h, Rep 2 |
| GSM6762186 |
PA21A092, Time 40h, Rep 2 |
| GSM6762187 |
PA21A092, Time 48h, Rep 2 |
| GSM6762188 |
PA21A092, Time 0h, Rep 3 |
| GSM6762189 |
PA21A092, Time 8h, Rep 3 |
| GSM6762190 |
PA21A092, Time 16h, Rep 3 |
| GSM6762191 |
PA21A092, Time 24h, Rep 3 |
| GSM6762192 |
PA21A092, Time 48h, Rep 3 |
| GSM6762193 |
PA21A092, Time 0h, Rep 4 |
| GSM6762194 |
PA21A092, Time 8h, Rep 4 |
| GSM6762195 |
PA21A092, Time 16h, Rep 4 |
| GSM6762196 |
PA21A092, Time 24h, Rep 4 |
| GSM6762197 |
PA21A092, Time 32h, Rep 4 |
| GSM6762198 |
PA21A092, Time 40h, Rep 4 |
| GSM6762199 |
PA21A092, Time 48h, Rep 4 |
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| Relations |
| BioProject |
PRJNA906537 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE218998_RAW.tar |
41.2 Mb |
(http)(custom) |
TAR (of TXT) |
| Processed data included within Sample table |
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