Identification of antimalarial compounds that inhibit Apicomplexan AP2 transcription factor proteins in the human malaria parasite Plasmodium falciparum
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PROVIDER: PRJNA837583 | ENA |
REPOSITORIES: ENA
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Project description:Plasmodium parasites are reliant on the Apicomplexan AP2 (ApiAP2) transcription factor family to regulate gene expression programs. AP2 DNA binding domains have no homologs in the human or mosquito host genomes, making them potential antimalarial drug targets. Using an in-silico screen to dock thousands of small molecules into the crystal structure of the AP2-EXP (Pf3D7_1466400) AP2 domain (PDB:3IGM), we identified compounds that interact with this domain. Four compounds were found to compete for DNA binding with AP2-EXP and at least one additional ApiAP2 protein. Our top ApiAP2 competitor compound perturbs the transcriptome of P. falciparum trophozoites and results in a decrease in abundance of log2 fold change > 2 for 50% (46/93) of AP2-EXP target genes. Additionally, two ApiAP2 competitor compounds have multi-stage anti-Plasmodium activity against blood and mosquito stage parasites. In summary, we describe a novel set of antimalarial compounds that are targeted against the ApiAP2 family of proteins. These compounds may be used for future chemical genetic interrogation of ApiAP2 proteins or serve as starting points for a new class of antimalarial therapeutics.
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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
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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
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Project description:Malarial parasite pathogenicity results from its ability to invade and remodel red blood cells (RBCs), expressing antigenic variant proteins for immune evasion and survival, and then to egress from the host cell. These sequential processes require concerted actions of a large number of proteins during the intraerythrocytic developmental cycle (IDC), but the molecular basis of the required regulation is only partially understood. Here, we have characterized an essential Apicomplexan AP2 (ApiAP2) transcription factor (we refer to it as PfAP2-P; Pathogenesis) that shows two peaks of expression during the IDC at 16- and 40-hour post invasion (h.p.i.). When expression of PfAP2-P at 40 h.p.i. was disrupted using an inducible gene knockout approach, ∆PfAP2-P parasites unable to form mature merozoites and egress from the host RBCs owing to strong down-regulation of several known egress- and invasion-associated genes, in addition to several novel hypothetical genes of thought to be involved in these key life cycle processes during the IDC. Disruption of PfAP2-P expression at 16 h.p.i. results in transcriptional activation of virtually majority of silenced var genes observed at both bulk and single cell level. This is also reflected by significantly higher level of recognition of the exported proteins on the ∆PfAP2-P parasite-infected RBCs by pooled sera from malaria-exposed individuals from endemic region. In addition, over-expression of many early gametocyte marker genes was also observed in ∆PfAP2-P parasites at both 40 h.p.i., and at 16 h.p.i. PfAP2-P directly regulates these genes by binding to their promoter region or indirectly through 14 other down-stream AP2 transcription factors. Taken together, we conclude that PfAP2-P is an upstream transcriptional regulator that participates in mutually exclusive expression pattern shown by the var family of genes and a critical determinant of parasite’s growth during the IDC.
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Project description:Malarial parasite pathogenicity results from its ability to invade and remodel red blood cells (RBCs), expressing antigenic variant proteins for immune evasion and survival, and then to egress from the host cell. These sequential processes require concerted actions of a large number of proteins during the intraerythrocytic developmental cycle (IDC), but the molecular basis of the required regulation is only partially understood. Here, we have characterized an essential Apicomplexan AP2 (ApiAP2) transcription factor (we refer to it as PfAP2-P; Pathogenesis) that shows two peaks of expression during the IDC at 16- and 40-hour post invasion (h.p.i.). When expression of PfAP2-P at 40 h.p.i. was disrupted using an inducible gene knockout approach, ∆PfAP2-P parasites unable to form mature merozoites and egress from the host RBCs owing to strong down-regulation of several known egress- and invasion-associated genes, in addition to several novel hypothetical genes of thought to be involved in these key life cycle processes during the IDC. Disruption of PfAP2-P expression at 16 h.p.i. results in transcriptional activation of virtually majority of silenced var genes observed at both bulk and single cell level. This is also reflected by significantly higher level of recognition of the exported proteins on the ∆PfAP2-P parasite-infected RBCs by pooled sera from malaria-exposed individuals from endemic region. In addition, over-expression of many early gametocyte marker genes was also observed in ∆PfAP2-P parasites at both 40 h.p.i., and at 16 h.p.i. PfAP2-P directly regulates these genes by binding to their promoter region or indirectly through 14 other down-stream AP2 transcription factors. Taken together, we conclude that PfAP2-P is an upstream transcriptional regulator that participates in mutually exclusive expression pattern shown by the var family of genes and a critical determinant of parasite’s growth during the IDC.
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Project description:Malarial parasite pathogenicity results from its ability to invade and remodel red blood cells (RBCs), expressing antigenic variant proteins for immune evasion and survival, and then to egress from the host cell. These sequential processes require concerted actions of a large number of proteins during the intraerythrocytic developmental cycle (IDC), but the molecular basis of the required regulation is only partially understood. Here, we have characterized an essential Apicomplexan AP2 (ApiAP2) transcription factor (we refer to it as PfAP2-P; Pathogenesis) that shows two peaks of expression during the IDC at 16- and 40-hour post invasion (h.p.i.). When expression of PfAP2-P at 40 h.p.i. was disrupted using an inducible gene knockout approach, ∆PfAP2-P parasites unable to form mature merozoites and egress from the host RBCs owing to strong down-regulation of several known egress- and invasion-associated genes, in addition to several novel hypothetical genes of thought to be involved in these key life cycle processes during the IDC. Disruption of PfAP2-P expression at 16 h.p.i. results in transcriptional activation of virtually majority of silenced var genes observed at both bulk and single cell level. This is also reflected by significantly higher level of recognition of the exported proteins on the ∆PfAP2-P parasite-infected RBCs by pooled sera from malaria-exposed individuals from endemic region. In addition, over-expression of many early gametocyte marker genes was also observed in ∆PfAP2-P parasites at both 40 h.p.i., and at 16 h.p.i. PfAP2-P directly regulates these genes by binding to their promoter region or indirectly through 14 other down-stream AP2 transcription factors. Taken together, we conclude that PfAP2-P is an upstream transcriptional regulator that participates in mutually exclusive expression pattern shown by the var family of genes and a critical determinant of parasite’s growth during the IDC.
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