ArticleAntimicrobial agents and chemotherapy2015
A chemical rescue screen identifies a Plasmodium falciparum apicoplast inhibitor targeting MEP isoprenoid precursor biosynthesis.
Article in Antimicrobial agents and chemotherapy, 2015. 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.
- Effect of Stereochemistry on the Antiplasmodial Activity and Metabolomic Profile of Novel Tadalafil Analogues.ACS medicinal chemistry letters · 2026Article
- β-Carboline: a privileged scaffold from nature for potential antimalarial activity.RSC medicinal chemistry · 2025Review
- Host-Derived Geranylgeraniol Shields Intraerythrocytic Stages of Malaria Parasites from Fosmidomycin.Research square · 2025Article
- Dissecting apicoplast functions through continuous cultivation of Toxoplasma gondii devoid of the organelle.Nature communications · 2025Article
- Targeting IspD for Anti-infective and Herbicide Development: Exploring Its Role, Mechanism, and Structural Insights.Journal of medicinal chemistry · 2025Review
- TargetingJournal of medicinal chemistry · 2024Article
- Beyond the MEP Pathway: A novel kinase required for prenol utilization by malaria parasites.PLoS pathogens · 2024Article
- MyosinA is a druggable target in the widespread protozoan parasite Toxoplasma gondii.PLoS biology · 2023Article
- New insights into apicoplast metabolism in blood-stage malaria parasites.Current opinion in microbiology · 2023Review
- Recent metabolomic developments for antimalarial drug discovery.Parasitology research · 2022Review
- Roles of the apicoplast across the life cycles of rodent and human malaria parasites.The Journal of eukaryotic microbiology · 2022Review
- Discovery of novel drug-like antitubercular hits targeting the MEP pathway enzyme DXPS by strategic application of ligand-based virtual screening.Chemical science · 2022Article
- Synthesis, Structure−Activity Relationships, and Parasitological Profiling of Brussonol Derivatives as New Plasmodium falciparum InhibitorsPharmaceuticals (Basel, Switzerland) · 2022Article
- Characterization of Domiphen Bromide as a New Fast-Acting Antiplasmodial Agent Inhibiting the Apicoplastidic Methyl Erythritol Phosphate Pathway.Pharmaceutics · 2022Article
- The Plasmodium falciparum ABC transporter ABCI3 confers parasite strain-dependent pleiotropic antimalarial drug resistance.Cell chemical biology · 2022Article
- Malaria Box-Inspired Discovery ofACS medicinal chemistry letters · 2022Article
- Enantiopure Benzofuran-2-carboxamides of 1-Aryltetrahydro-β-carbolines Are Potent AntimalarialsACS medicinal chemistry letters · 2022Article
- Antiplasmodial activity of the natural product compounds alstonine and himbeline.International journal for parasitology. Drugs and drug resistance · 2021Article
- Essential Genes of the Parasitic Apicomplexa.Trends in parasitology · 2021Review
- Probing the B- & C-rings of the antimalarial tetrahydro-β-carboline MMV008138 for steric and conformational constraints.Bioorganic & medicinal chemistry letters · 2020Article
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Abstract
The apicoplast is an essential plastid organelle found in Plasmodium parasites which contains several clinically validated antimalarial-drug targets. A chemical rescue screen identified MMV-08138 from the "Malaria Box" library of growth-inhibitory antimalarial compounds as having specific activity against the apicoplast. MMV-08138 inhibition of blood-stage Plasmodium falciparum growth is stereospecific and potent, with the most active diastereomer demonstrating a 50% effective concentration (EC50) of 110 nM. Whole-genome sequencing of 3 drug-resistant parasite populations from two independent selections revealed E688Q and L244I mutations in P. falciparum IspD, an enzyme in the MEP (methyl-d-erythritol-4-phosphate) isoprenoid precursor biosynthesis pathway in the apicoplast. The active diastereomer of MMV-08138 directly inhibited PfIspD activity in vitro with a 50% inhibitory concentration (IC50) of 7.0 nM. MMV-08138 is the first PfIspD inhibitor to be identified and, together with heterologously expressed PfIspD, provides the foundation for further development of this promising antimalarial drug candidate lead. Furthermore, this report validates the use of the apicoplast chemical rescue screen coupled with target elucidation as a discovery tool to identify specific apicoplast-targeting compounds with new mechanisms of action.
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