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| Status |
Public on Jan 27, 2021 |
| Title |
Metabolic survival adaptations of Plasmodium falciparum exposed to sub-lethal doses of fosmidomycin |
| Organism |
Plasmodium falciparum |
| Experiment type |
Expression profiling by array
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| Summary |
The malaria parasite Plasmodium falciparum contains the apicoplast organelle that synthesize isoprenoids, which are metabolites necessary for post-translational modification of Plasmodium proteins. We used fosmidomycin, an antibiotic that inhibits isoprenoid biosynthesis, to identify mechanisms that underlie the development of the parasite’s adaptation to the drug at sub-lethal concentrations. We first determined a concentration of fosmidomycin that reduced parasite growth by ~50% over one intraerythrocytic developmental cycle (IDC). At this dose, we maintained synchronous parasite cultures for one full IDC, and collected metabolomic and transcriptomic data at multiple time points to capture global and stage-specific alterations. We integrated the data with a genome-scale metabolic model of P. falciparum to characterize the metabolic adaptations of the parasite in response to fosmidomycin treatment. Our simulations showed that, in treated parasites, the synthesis of purine-based nucleotides increased, whereas the synthesis of phosphatidylcholine during the trophozoite and schizont stages decreased. Specifically, the increased polyamine synthesis led to increased nucleotide synthesis, while the reduced methyl-group cycling led to reduced phospholipid synthesis and methyltransferase activities. These results indicate that fosmidomycin-treated parasites compensate for the loss of prenylation modifications by directly altering processes that affect nucleotide synthesis and ribosomal biogenesis to control the rate of RNA translation during the IDC. This also suggests that combination therapies with antibiotics that target the compensatory response of the parasite, such as nucleotide synthesis or ribosomal biogenesis, may be more effective than treating the parasite with fosmidomycin alone.
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| Overall design |
PfNF54 parasites were cultured for 48 hours in the presence of sub-lethal dose of fosmidomycin with samples taken every eight hours for transcriptomics and processed in quadruplicate, except for Time 0 Rep 3.
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| Contributor(s) |
Tewari SG, Rajaram K, Swift RP, Dziedzic A, Jedlicka AE, Reifman J, Prigge ST, Wallqvist A |
| Citation(s) |
33495219 |
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| Submission date |
Oct 19, 2020 |
| Last update date |
Jan 30, 2021 |
| 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 (27)
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| GSM4831638 |
Time 24h, Rep 1 |
| GSM4831639 |
Time 32h, Rep 1 |
| GSM4831640 |
Time 40h, Rep 1 |
| GSM4831641 |
Time 48h, Rep 1 |
| GSM4831642 |
Time 0h, Rep 2 |
| GSM4831643 |
Time 8h, Rep 2 |
| GSM4831644 |
Time 16h, Rep 2 |
| GSM4831645 |
Time 24h, Rep 2 |
| GSM4831646 |
Time 32h, Rep 2 |
| GSM4831647 |
Time 40h, Rep 2 |
| GSM4831648 |
Time 48h, Rep 2 |
| GSM4831649 |
Time 8h, Rep 3 |
| GSM4831650 |
Time 16h, Rep 3 |
| GSM4831651 |
Time 24h, Rep 3 |
| GSM4831652 |
Time 32h, Rep 3 |
| GSM4831653 |
Time 40h, Rep 3 |
| GSM4831654 |
Time 48h, Rep 3 |
| GSM4831655 |
Time 0h, Rep 4 |
| GSM4831656 |
Time 8h, Rep 4 |
| GSM4831657 |
Time 16h, Rep 4 |
| GSM4831658 |
Time 24h, Rep 4 |
| GSM4831659 |
Time 32h, Rep 4 |
| GSM4831660 |
Time 40h, Rep 4 |
| GSM4831661 |
Time 48h, Rep 4 |
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| Relations |
| BioProject |
PRJNA670026 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE159516_RAW.tar |
21.2 Mb |
(http)(custom) |
TAR (of TXT) |
| Processed data included within Sample table |
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