ArticleMolecular microbiology2016
CRISPR-Cas9-modified pfmdr1 protects Plasmodium falciparum asexual blood stages and gametocytes against a class of piperazine-containing compounds but potentiates artemisinin-based combination therapy partner drugs.
Article in Molecular microbiology, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 47 papers.
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Who cites it
47 citing papers in PubMed, 67 citations in OpenAlex.
- Structural and mechanistic insights into the inhibition of Plasmodium falciparum MDR1.Nature communications · 2026Article
- Collateral hypersensitivity between ZY19489 and piperaquine neutralizes PfCRT-mediated drug efflux and Plasmodium falciparum resistance.Nature communications · 2026Article
- Disruption of P. falciparum amino acid transporter elevates intracellular proline and induces resistance to Prolyl-tRNA synthetase inhibitors.Cell chemical biology · 2025Article
- The plasmepsin-piperaquine paradox persists in Plasmodium falciparum.PLoS pathogens · 2025Article
- Stereospecific Resistance to N2-Acyl Tetrahydro-β-carboline Antimalarials Is Mediated by a PfMDR1 Mutation That Confers Collateral Drug Sensitivity.ACS infectious diseases · 2025Article
- Uncovering the Mechanism of Action of Antiprotozoal Agents: A Survey on Photoaffinity Labeling Strategy.Pharmaceuticals (Basel, Switzerland) · 2024Review
- Systematic in vitro evolution inScience (New York, N.Y.) · 2024Article
- Enhanced cell stress response and protein degradation capacity underlie artemisinin resistance inmSphere · 2024Article
- Eliminating malaria transmission requires targeting immature and mature gametocytes through lipoidal uptake of antimalarials.Nature communications · 2024Article
- Antiplasmodial peptaibols act through membrane directed mechanisms.Cell chemical biology · 2024Article
- Antimalarial drug discovery: progress and approaches.Nature reviews. Drug discovery · 2023Review
- High-content imaging as a tool to quantify and characterize malaria parasites.Cell reports methods · 2023Article
- Potent acyl-CoA synthetase 10 inhibitors kill Plasmodium falciparum by disrupting triglyceride formation.Nature communications · 2023Article
- The Nitrobenzoxadiazole Derivative NBDHEX Behaves asPharmaceuticals (Basel, Switzerland) · 2022Article
- Protecting future antimalarials from the trap of resistance: Lessons from artemisinin-based combination therapy (ACT) failures.Journal of pharmaceutical analysis · 2021Review
- Properties of Plasmodium falciparum with a Deleted Apicoplast DNA Gyrase.Antimicrobial agents and chemotherapy · 2021Article
- Assessing risks of Plasmodium falciparum resistance to select next-generation antimalarials.Trends in parasitology · 2021Review
- Balanced impacts of fitness and drug pressure on the evolution of PfMDR1 polymorphisms in Plasmodium falciparum.Malaria journal · 2021Article
- Genomic and Genetic Approaches to Studying Antimalarial Drug Resistance and Plasmodium Biology.Trends in parasitology · 2021Review
- CRISPR/Cas9 Ribonucleoprotein-Based Genome Editing Methodology in the Marine Protozoan ParasiteFrontiers in bioengineering and biotechnology · 2021Article
Corrections and comments
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Authors and funding
14 authors at 5 institutions in 3 countries.
Funding
Abstract
Emerging resistance to first-line antimalarial combination therapies threatens malaria treatment and the global elimination campaign. Improved therapeutic strategies are required to protect existing drugs and enhance treatment efficacy. We report that the piperazine-containing compound ACT-451840 exhibits single-digit nanomolar inhibition of the Plasmodium falciparum asexual blood stages and transmissible gametocyte forms. Genome sequence analyses of in vitro-derived ACT-451840-resistant parasites revealed single nucleotide polymorphisms in pfmdr1, which encodes a digestive vacuole membrane-bound ATP-binding cassette transporter known to alter P. falciparum susceptibility to multiple first-line antimalarials. CRISPR-Cas9 based gene editing confirmed that PfMDR1 point mutations mediated ACT-451840 resistance. Resistant parasites demonstrated increased susceptibility to the clinical drugs lumefantrine, mefloquine, quinine and amodiaquine. Stage V gametocytes harboring Cas9-introduced pfmdr1 mutations also acquired ACT-451840 resistance. These findings reveal that PfMDR1 mutations can impart resistance to compounds active against asexual blood stages and mature gametocytes. Exploiting PfMDR1 resistance mechanisms provides new opportunities for developing disease-relieving and transmission-blocking antimalarials.
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Registered trials
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