Abstract
BackgroundIn recent years, a major increase in the occurrence of drug resistant falciparum malaria has been reported. Choline analogs, such as the bisthiazolium T4, represent a novel class of compounds with strong potency against drug sensitive and resistant P. falciparum clones. Although T4 and its analogs are presumed to target the parasite's lipid metabolism, their exact mechanism of action remains unknown. Here we have employed transcriptome and proteome profiling analyses to characterize the global response of P. falciparum to T4 during the intraerythrocytic cycle of this parasite.ResultsNo significant transcriptional changes were detected immediately after addition of T4 despite the drug's effect on the parasite metabolism. Using the Ontology-based Pattern Identification (OPI) algorithm with an increased T4 incubation time, we demonstrated cell cycle arrest and a general induction of genes involved in gametocytogenesis. Proteomic analysis revealed a significant decrease in the level of the choline/ethanolamine-phosphotransferase (PfCEPT), a key enzyme involved in the final step of synthesis of phosphatidylcholine (PC). This effect was further supported by metabolic studies, which showed a major alteration in the synthesis of PC from choline and ethanolamine by the compound.ConclusionOur studies demonstrate that the bisthiazolium compound T4 inhibits the pathways of synthesis of phosphatidylcholine from choline and ethanolamine in P. falciparum, and provide evidence for post-transcriptional regulations of parasite metabolism in response to external stimuli.
Highlights
Malaria remains a major public health problem in many parts of the world
T4 treatment for 30 and 36 hours resulted in increased transcriptional changes with 1140 and 1825 genes differentially expressed, respectively (See Additional file 3)
The correlation coefficients observed between transcripts at different stages of the P. falciparum cell cycle without treatment changed significantly (i.e., 24 hours/30 hours, r = 0.64; 30 hours/36 hours, r = 0.95 and 24 hours/ 36 hours, r = 0.95)
Summary
Malaria remains a major public health problem in many parts of the world. Emergence and spread of resistance to widely accessible and inexpensive antimalarials make the development of novel therapeutic approaches an urgent task [1,2]. Phosphatidylcholine (PC) is the major phospholipid in P. falciparum membranes and its content increases by approximately six-fold during the parasite's intraerythrocytic life cycle [3,4]. Cell biological studies revealed that the synthesis of this phospholipid occurs via two major metabolic pathways: the de novo choline pathway and the serine decarboxylation-phospho-ethanolamine methylation (SDPM) pathway (Figure 1). A major increase in the occurrence of drug resistant falciparum malaria has been reported. Choline analogs, such as the bisthiazolium T4, represent a novel class of compounds with strong potency against drug sensitive and resistant P. falciparum clones. We have employed transcriptome and proteome profiling analyses to characterize the global response of P. falciparum to T4 during the intraerythrocytic cycle of this parasite
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