Effect of choline kinase inhibitor hexadecyltrimethylammonium bromide on Plasmodium falciparum gene expression
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ABSTRACT:
ORGANISM(S): Plasmodium falciparum Anopheles gambiae
PROVIDER: GSE54775 | GEO | 2014/02/08
SECONDARY ACCESSION(S): PRJNA237602
REPOSITORIES: GEO
Similar Datasets
Project description:Investigations on the fundamental of malaria parasite biology, such as invasion, growth cycle, metabolism and cell signalling have uncovered a number of potential antimalarial drug targets, including choline kinase, a key enzyme involved in the synthesis of phosphatidylcholine, an important component in parasite membrane compartment. The effect on gene expression of Plasmodium falciparum K1 strain following 72 hours exposure to 2 M-NM-<M (IC50 concentration) of the choline kinase inhibitor, hexadecyltrimethylammonium bromide (HDTAB) was evaluated by DNA microarray analysis. Genes important in P. falciparum intra-erythrocytic life cycle, such as invasion, cytoadherance and growth were among those affected by at least 2-fold changes in their expression levels compared with non HDTAB-treated control. Two different cultures of P. falciparum was divided into two groups, untreated and HDTAB treated. The parasites were incubated for 72 hours and harvested for total RNA extraction. The expression profile was analysed by microarray.
2014-02-08 | E-GEOD-54775 | biostudies-arrayexpress
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: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:Choline analogs represent a novel class of antimalarial compounds with strong potency against drug-sensitive and resistant P. falciparum. Although, these drugs are presumed to target proteins within lipid biosynthesis pathways; their complete mechanism of action and the parasite’s compensatory response remain to be elucidated. We have applied transcriptional profiling to characterize the global response to the choline analog T4 during the P. falciparum intraerythrocytic life cycle Keywords: Trascriptome analysis of Plasmodium falciparum in response to external stimuli using the affymetrix platform GPL3575
2007-07-31 | GSE4582 | 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:Effect of choline kinase inhibitor hexadecyltrimethylammonium bromide on Plasmodium falciparum gene expression
| PRJNA237602 | ENA
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:The development of the human malaria parasite Plasmodium falciparum is controlled by coordinated changes in gene expression throughout its complex life cycle, but the corresponding regulatory mechanisms are incompletely understood. To study the relation between genome architecture and gene regulation in Plasmodium, we studied the genome structure of P. falciparum at three time points during its erythrocytic (asexual) cycle. Using chromosome conformation capture coupled with next-generation sequencing technology (Hi-C), we obtained high-resolution chromosomal contact maps, which we then used to construct a consensus three-dimensional genome structure for each time point. We observe strong clustering of centromeres, telomeres, ribosomal DNA and virulence genes, resulting in a complex architecture that cannot be explained by a simple volume exclusion model. Internal virulence gene clusters appear to be an important factor in shaping the genome architecture as they exhibit domain-like structures similar to topological domains in mammalian genomes. Midway during the cell cycle, at the highly transcriptionally active trophozoite stage, the genome adopts a more open chromatin structure with increased chromosomal intermingling. In addition, we observed reduced expression of genes located in spatial proximity to the repressive subtelomeric center, and colocalization of distinct groups of parasite-specific genes with coordinated expression profiles. Overall, our results are indicative of a strong association between the P. falciparum spatial genome organization and gene expression. Understanding the molecular processes involved in genome conformation dynamics could contribute to the discovery of novel antimalarial strategies. Analysis of the spatial organization of the P. falciparum genome at three stages of the erythrocytic cycle using chromosome conformation capture coupled with next generation sequencing (Hi-C). As a control, we included one sample for which chromatin contacts were not preserved by crosslinking of DNA and proteins.
2014-01-06 | E-GEOD-50199 | biostudies-arrayexpress
Project description:Calcium Dependent Protein Kinases (CDPKs) are key effectors of calcium signaling in malaria parasite. We have elucidated a novel role of PfCDPK1, which is indispensable for the erythrocytic development of Plasmodium falciparum, in invasion of host Red Blood Cells (RBCs). To gain insights into the mechanisms via which PfCDPK1 is involved in parasitic processes, a comparative phosphoproteomic analysis was employed to identify its parasitic targets. Proteins were isolated from CDPK1 knockdown and wild type parasites and processed for trypsin digestion and iTRAQ labeling. Quantitative proteomic analysis using high resolution mass spectrometry led to the identification of hypophosphorylated proteins, which can be the likely substrates for this kinase. In addition, in vitro kinase assays and antibody based validation of the hypophosphorylated sites was carried out. This study will provide a novel insight into the CDPK1 mediated invasion by Plasmodium falciparum.
2017-05-02 | PXD005207 | Pride
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