ArticlePLoS biology2019
Delayed death in the malaria parasite Plasmodium falciparum is caused by disruption of prenylation-dependent intracellular trafficking.
Article in PLoS biology, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 54 papers.
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Who cites it
54 citing papers in PubMed, 118 citations in OpenAlex.
- Review
- Identification of genetic markers of quinine partial resistance in Plasmodium falciparum.Nature microbiology · 2026Article
- Sortase A-Mediated Farnesylation of Cdc42ACS synthetic biology · 2026Article
- Identification of a Putative Metal Transporter in the Apicoplast of Malaria Parasites.bioRxiv : the preprint server for biology · 2026Article
- An essential adaptor for apicoplast fission and inheritance in malaria parasites.Nature communications · 2025Article
- An Essential Adaptor for Apicoplast Fission and Inheritance in Malaria Parasites.bioRxiv : the preprint server for biology · 2025Article
- Hexosamine biosynthesis disruption impairs GPI production and arrests Plasmodium falciparum growth at schizont stages.PLoS pathogens · 2025Article
- Host-Derived Geranylgeraniol Shields Intraerythrocytic Stages of Malaria Parasites from Fosmidomycin.Research square · 2025Article
- From Traditional Amazon Use to Food Applications:Foods (Basel, Switzerland) · 2025Article
- Functional dissection of prenyltransferases reveals roles in endocytosis and secretory vacuolar sorting in type 2-ME49 strain ofVirulence · 2024Article
- Identification of a divalent metal transporter required for cellular iron metabolism in malaria parasites.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- A kalihinol analog disrupts apicoplast function and vesicular trafficking inScience (New York, N.Y.) · 2024Article
- Apicoplast-derived isoprenoids are essential for biosynthesis of GPI protein anchors, and consequently for egress and invasion in Plasmodium falciparum.PLoS pathogens · 2024Article
- The artemisinin-induced dormant stages of Plasmodium falciparum exhibit hallmarks of cellular quiescence/senescence and drug resilience.Nature communications · 2024Article
- Cell Death ofPathogens (Basel, Switzerland) · 2024Article
- A picomolar inhibitor of theAntimicrobial agents and chemotherapy · 2024Article
- Identification of a divalent metal transporter required for cellular iron metabolism in malaria parasites.bioRxiv : the preprint server for biology · 2024Article
- TheeLife · 2024Article
- Apicoplast-Resident Processes: Exploiting the Chink in the Armour ofAdvances in pharmacological and pharmaceutical sciences · 2024Review
- Beyond the MEP Pathway: A novel kinase required for prenol utilization by malaria parasites.PLoS pathogens · 2024Article
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Authors and funding
11 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Apicomplexan parasites possess a plastid organelle called the apicoplast. Inhibitors that selectively target apicoplast housekeeping functions, including DNA replication and protein translation, are lethal for the parasite, and several (doxycycline, clindamycin, and azithromycin) are in clinical use as antimalarials. A major limitation of such drugs is that treated parasites only arrest one intraerythrocytic development cycle (approximately 48 hours) after treatment commences, a phenotype known as the 'delayed death' effect. The molecular basis of delayed death is a long-standing mystery in parasitology, and establishing the mechanism would aid rational clinical implementation of apicoplast-targeted drugs. Parasites undergoing delayed death transmit defective apicoplasts to their daughter cells and cannot produce the sole, blood-stage essential metabolic product of the apicoplast: the isoprenoid precursor isopentenyl-pyrophosphate. How the isoprenoid precursor depletion kills the parasite remains unknown. We investigated the requirements for the range of isoprenoids in the human malaria parasite Plasmodium falciparum and characterised the molecular and morphological phenotype of parasites experiencing delayed death. Metabolomic profiling reveals disruption of digestive vacuole function in the absence of apicoplast derived isoprenoids. Three-dimensional electron microscopy reveals digestive vacuole fragmentation and the accumulation of cytostomal invaginations, characteristics common in digestive vacuole disruption. We show that digestive vacuole disruption results from a defect in the trafficking of vesicles to the digestive vacuole. The loss of prenylation of vesicular trafficking proteins abrogates their membrane attachment and function and prevents the parasite from feeding. Our data show that the proximate cause of delayed death is an interruption of protein prenylation and consequent cellular trafficking defects.
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