ArticleProceedings of the National Academy of Sciences of the United States of America2014
Diverse mutational pathways converge on saturable chloroquine transport via the malaria parasite's chloroquine resistance transporter.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 48 papers.
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Who cites it
48 citing papers in PubMed.
- High-Dose Chloroquine for Uncomplicated Plasmodium falciparum Malaria Is Well Tolerated and Causes Similar QT Interval Prolongation as Standard-Dose Chloroquine in Children.Antimicrobial agents and chemotherapy · 2020Trial
- Temporal and seasonal changes of genetic polymorphisms associated with altered drug susceptibility to chloroquine, lumefantrine, and quinine in Guinea-Bissau between 2003 and 2012.Antimicrobial agents and chemotherapy · 2015Trial
- Gain-of-function PfAAT1 mutations compensate for impaired PfCRT function inResearch square · 2026Article
- Article
- Thymol Derivatives as Antimalarial Agents: Synthesis, Activity AgainstBiomedicines · 2026Article
- Role of novel mutations in food vacuole transporters beyond K13-mediated artemisinin resistance inAntimicrobial agents and chemotherapy · 2025Article
- No evidence of molecular markers of piperaquine resistance in southeastern Nigeria.Malaria journal · 2025Article
- Geographical Heterogeneity in Antimalarial Resistance Markers Revealed by Genomic Surveillance in Angola, 2023.medRxiv : the preprint server for health sciences · 2025Article
- Molecular basis of the functional conflict between chloroquine and peptide transport in the Malaria parasite chloroquine resistance transporter PfCRT.Nature communications · 2025Article
- Assessing fitness costs in malaria parasites: a comprehensive review and implications for drug resistance management.Malaria journal · 2025Review
- Molecular survey of pfmdr-1, pfcrt, and pfk13 gene mutations among patients returning from Plasmodium falciparum endemic areas to Turkey.Malaria journal · 2024Article
- pH-dependence of the Plasmodium falciparum chloroquine resistance transporter is linked to the transport cycle.Nature communications · 2023Article
- PfCRT mutations conferring piperaquine resistance in falciparum malaria shape the kinetics of quinoline drug binding and transport.PLoS pathogens · 2023Article
- The role of SWEET4 proteins in the post-phloem sugar transport pathway of Setaria viridis sink tissues.Journal of experimental botany · 2023Article
- Mechanistic basis for multidrug resistance and collateral drug sensitivity conferred to the malaria parasite by polymorphisms in PfMDR1 and PfCRT.PLoS biology · 2022Article
- Chloroquine-susceptible and -resistant Plasmodium falciparum strains survive high chloroquine concentrations by becoming dormant but are eliminated by prolonged exposure.The Journal of antimicrobial chemotherapy · 2022Article
- Evidence for the early emergence of piperaquine-resistant Plasmodium falciparum malaria and modeling strategies to mitigate resistance.PLoS pathogens · 2022Article
- Inferring a complete genotype-phenotype map from a small number of measured phenotypes.PLoS computational biology · 2020Article
- Article
- The natural function of the malaria parasite's chloroquine resistance transporter.Nature communications · 2020Article
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Authors and funding
14 authors.
Funding
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Abstract
Mutations in the chloroquine resistance transporter (PfCRT) are the primary determinant of chloroquine (CQ) resistance in the malaria parasite Plasmodium falciparum. A number of distinct PfCRT haplotypes, containing between 4 and 10 mutations, have given rise to CQ resistance in different parts of the world. Here we present a detailed molecular analysis of the number of mutations (and the order of addition) required to confer CQ transport activity upon the PfCRT as well as a kinetic characterization of diverse forms of PfCRT. We measured the ability of more than 100 variants of PfCRT to transport CQ when expressed at the surface of Xenopus laevis oocytes. Multiple mutational pathways led to saturable CQ transport via PfCRT, but these could be separated into two main lineages. Moreover, the attainment of full activity followed a rigid process in which mutations had to be added in a specific order to avoid reductions in CQ transport activity. A minimum of two mutations sufficed for (low) CQ transport activity, and as few as four conferred full activity. The finding that diverse PfCRT variants are all limited in their capacity to transport CQ suggests that resistance could be overcome by reoptimizing the CQ dosage.
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