Plasmodium falciparum
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA918715 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR27689700_1.fastq.gz | Fastqsanger.gz | |||
| SRR27689700_2.fastq.gz | Fastqsanger.gz | |||
| SRR27689800_1.fastq.gz | Fastqsanger.gz | |||
| SRR27689800_2.fastq.gz | Fastqsanger.gz | |||
| SRR27689701_1.fastq.gz | Fastqsanger.gz |
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Project description:Artemisinin and its derivatives exert the potent, antimalarial action, although the mechanisms by which these drugs inhibit the growth of mararia parasites is not fully understood. We used microarrays to detail the global gene expression change in early erythrocytic P. falciparum, and identified molecules that may contribute to the activity of dihydroartemisinin.
2020-11-30 | GSE160666 | GEO
Project description:Transcriptional profiling of P. falciparum cultures treated with cyclohexylamine over time (18, 25 and 30 hours post invasion) A control experiment was also set up in which P. falciparum was not treated with cyclohexylamine, and samples were taken at 18, 25 and 30 h post invasion). Background Plasmodium falciparum, the causative agent of severe human malaria, has evolved to become resistant to previously successful antimalarial chemotherapies, most notably chloroquine and the antifolates. The prevalence of resistant strains has necessitated the discovery and development of new chemical entities with novel modes-of-action. Although much effort has been invested in the creation of analogues based on existing drugs and the screening of chemical and natural compound libraries, a crucial shortcoming in current Plasmodial drug discovery efforts remains the lack of an extensive set of novel, validated drug targets. A requirement of these targets (or the pathways in which they function) is that they prove essential for parasite survival. The polyamine biosynthetic pathway, responsible for the metabolism of highly abundant amines crucial for parasite growth, proliferation and differentiation, is currently under investigation as an antimalarial target. Chemotherapeutic strategies targeting this pathway have been successfully utilized for the treatment of Trypanosomes causing West African sleeping sickness. In order to further evaluate polyamine depletion as possible antimalarial intervention, the consequences of inhibiting P. falciparum spermidine synthase (PfSpdSyn) were examined on a morphological, transcriptomic, proteomic and metabolic level. Results Morphological analysis of P. falciparum 3D7 following application of the PfSpdSyn inhibitor cyclohexylamine confirmed that parasite development was completely arrested at the early trophozoite stage. This is in contrast to untreated parasites which progressed to late trophozoites at comparable time points. Global gene expression analyses confirmed a transcriptional arrest in the parasite. Several of the differentially expressed genes mapped to the polyamine biosynthetic and associated metabolic pathways. Differential expression of corresponding parasite proteins involved in polyamine biosynthesis was also observed. Most notably, uridine phosphorylase, adenosine deaminase, lysine decarboxylase (LDC) and S-adenosylmethionine synthetase were differentially expressed at the transcript and/or protein level. Several genes in associated metabolic pathways (purine metabolism and various methyltransferases) were also affected. The specific nature of the perturbation was additionally reflected by changes in polyamine metabolite levels. Conclusions This study details the malaria parasite’s response to PfSpdSyn inhibition on the transcriptomic, proteomic and metabolic levels. The results corroborate and significantly expand previous functional genomics studies relating to polyamine depletion in this parasite. Moreover, they confirm the role of transcriptional regulation in P. falciparum, particularly in this pathway. The findings promote this essential pathway as a target for antimalarial chemotherapeutic intervention strategies. Keywords: Time course experiment in response to a drug treatment
2010-04-19 | GSE18075 | GEO
Project description:While many molecular changes associated with commonly used antimalarials are known, there remain important questions on how parasites arrive at the correct causal molecular solutions in a haploid genome. We selected for resistance to DSM1, a novel dihydroorotate dehydrogenase (DHODH) inhibitor with a non-biological triazolopyrimidine scaffold, in P. falciparum with the Accelerated Resistance to Multiple Drugs (ARMD) trait. While direct sequencing revealed no mutations in the target DHODH gene, comparative genomic hybridizations from four independently selected DSM1-resistant clones showed a large, single 34-95kb amplification in each clone. Each amplified region always included the DHODH locus. The length of this region and the resulting 2- to 3-fold DHODH copy number increase were verified at the RNA and protein level. DSM1 resistance was stable over several months of in vitro culture. Additional selection at higher DSM1 concentrations caused further gains in CNVs at the DHODH locus. The present system validated DHODH as a key target of the triazolopyrimidine antimalarial, DSM1 and, more importantly, captured large, random CNVs as an early step in the initiation of drug resistance in malaria parasites. This defined system is expected to be valuable for characterizing early, causal molecular steps leading to successful drug resistance RNA from P. falciparum DSM1 resistant cell-line was hybridized against RNA of parental strain, Dd2. DSM1 resistant cell culture was maintained under DSM1 at 333 nM, microarray data were obtained from three hybridizations using RNA from three independent parasite cultures
2013-05-01 | E-GEOD-35949 | biostudies-arrayexpress
Project description:While many molecular changes associated with commonly used antimalarials are known, there remain important questions on how parasites arrive at the correct causal molecular solutions in a haploid genome. We selected for resistance to DSM1, a novel dihydroorotate dehydrogenase (DHODH) inhibitor with a non-biological triazolopyrimidine scaffold, in P. falciparum with the Accelerated Resistance to Multiple Drugs (ARMD) trait. While direct sequencing revealed no mutations in the target DHODH gene, comparative genomic hybridizations from four independently selected DSM1-resistant clones showed a large, single 34-95kb amplification in each clone. Each amplified region always included the DHODH locus. The length of this region and the resulting 2- to 3-fold DHODH copy number increase were verified at the RNA and protein level. DSM1 resistance was stable over several months of in vitro culture. Additional selection at higher DSM1 concentrations caused further gains in CNVs at the DHODH locus. The present system validated DHODH as a key target of the triazolopyrimidine antimalarial, DSM1 and, more importantly, captured large, random CNVs as an early step in the initiation of drug resistance in malaria parasites. This defined system is expected to be valuable for characterizing early, causal molecular steps leading to successful drug resistance gDNA from P. falciparum DSM1 resistant cell-line was hybridized against gDNA of parental strain, Dd2. DSM1 resistant cell culture was maintained under DSM1 at 333 nM, microarray data were obtained from three hybridizations using gDNA from three independent parasite cultures
2013-05-01 | E-GEOD-35732 | biostudies-arrayexpress
Project description:While many molecular changes associated with commonly used antimalarials are known, there remain important questions on how parasites arrive at the correct causal molecular solutions in a haploid genome. We selected for resistance to DSM1, a novel dihydroorotate dehydrogenase (DHODH) inhibitor with a non-biological triazolopyrimidine scaffold, in P. falciparum with the Accelerated Resistance to Multiple Drugs (ARMD) trait. While direct sequencing revealed no mutations in the target DHODH gene, comparative genomic hybridizations from four independently selected DSM1-resistant clones showed a large, single 34-95kb amplification in each clone. Each amplified region always included the DHODH locus. The length of this region and the resulting 2- to 3-fold DHODH copy number increase were verified at the RNA and protein level. DSM1 resistance was stable over several months of in vitro culture. Additional selection at higher DSM1 concentrations caused further gains in CNVs at the DHODH locus. The present system validated DHODH as a key target of the triazolopyrimidine antimalarial, DSM1 and, more importantly, captured large, random CNVs as an early step in the initiation of drug resistance in malaria parasites. This defined system is expected to be valuable for characterizing early, causal molecular steps leading to successful drug resistance
2013-05-01 | GSE35949 | GEO
Project description:While many molecular changes associated with commonly used antimalarials are known, there remain important questions on how parasites arrive at the correct causal molecular solutions in a haploid genome. We selected for resistance to DSM1, a novel dihydroorotate dehydrogenase (DHODH) inhibitor with a non-biological triazolopyrimidine scaffold, in P. falciparum with the Accelerated Resistance to Multiple Drugs (ARMD) trait. While direct sequencing revealed no mutations in the target DHODH gene, comparative genomic hybridizations from four independently selected DSM1-resistant clones showed a large, single 34-95kb amplification in each clone. Each amplified region always included the DHODH locus. The length of this region and the resulting 2- to 3-fold DHODH copy number increase were verified at the RNA and protein level. DSM1 resistance was stable over several months of in vitro culture. Additional selection at higher DSM1 concentrations caused further gains in CNVs at the DHODH locus. The present system validated DHODH as a key target of the triazolopyrimidine antimalarial, DSM1 and, more importantly, captured large, random CNVs as an early step in the initiation of drug resistance in malaria parasites. This defined system is expected to be valuable for characterizing early, causal molecular steps leading to successful drug resistance
2013-05-01 | GSE35732 | GEO
Project description:Tetracyclines are effective but slow-acting antimalarial drugs whose mechanism of action remains uncertain. To characterize the antimalarial mechanism of tetracyclines, we evaluated their stage-specific activities, impacts on parasite transcription, and effects on two predicted organelle targets, the apicoplast and the mitochondrion, in cultured Plasmodium falciparum. Antimalarial effects were much greater after two 48-h life cycles than after one cycle, even if the drugs were removed at the end of the first cycle. Doxycycline-treated parasites appeared morphologically normal until late in the second cycle of treatment but failed to develop into merozoites. Doxycycline specifically impaired the expression of apicoplast genes. Apicoplast morphology initially appeared normal in the presence of doxycycline. However, apicoplasts were abnormal in the progeny of doxycycline-treated parasites, as evidenced by a block in apicoplast genome replication, a lack of processing of an apicoplast-targeted protein, and failure to elongate and segregate during schizogeny. Replication of the nuclear and mitochondrial genomes and mitochondrial morphology appeared normal. Our results demonstrate that tetracyclines specifically block expression of the apicoplast genome, resulting in the distribution of nonfunctional apicoplasts into daughter merozoites. The loss of apicoplast function in the progeny of treated parasites leads to a slow but potent antimalarial effect. We analyzed a series of 12 microarrays covering 55 hours of Plasmodium falciparum treated with doxycycline and 12 microarrays covering the same 55 hours with no doxycycline treatment
2010-07-01 | E-GEOD-5267 | biostudies-arrayexpress
Project description:Malaria in vitro drug resistance selection
| PRJNA242193 | ENA
Project description:Tetracyclines are effective but slow-acting antimalarial drugs whose mechanism of action remains uncertain. To characterize the antimalarial mechanism of tetracyclines, we evaluated their stage-specific activities, impacts on parasite transcription, and effects on two predicted organelle targets, the apicoplast and the mitochondrion, in cultured Plasmodium falciparum. Antimalarial effects were much greater after two 48-h life cycles than after one cycle, even if the drugs were removed at the end of the first cycle. Doxycycline-treated parasites appeared morphologically normal until late in the second cycle of treatment but failed to develop into merozoites. Doxycycline specifically impaired the expression of apicoplast genes. Apicoplast morphology initially appeared normal in the presence of doxycycline. However, apicoplasts were abnormal in the progeny of doxycycline-treated parasites, as evidenced by a block in apicoplast genome replication, a lack of processing of an apicoplast-targeted protein, and failure to elongate and segregate during schizogeny. Replication of the nuclear and mitochondrial genomes and mitochondrial morphology appeared normal. Our results demonstrate that tetracyclines specifically block expression of the apicoplast genome, resulting in the distribution of nonfunctional apicoplasts into daughter merozoites. The loss of apicoplast function in the progeny of treated parasites leads to a slow but potent antimalarial effect. Keywords: Plasmodium falciparum treated with Doxycycline
2006-07-11 | GSE5267 | GEO