ArticleThe Journal of infectious diseases2022
Decreased Susceptibility to Dihydrofolate Reductase Inhibitors Associated With Genetic Polymorphisms in Ugandan Plasmodium falciparum Isolates.
Article in The Journal of infectious diseases, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.
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Who cites it
6 citing papers in PubMed, 11 citations in OpenAlex.
- Trial
- Multiple local PfDHFR I164L haplotype expansions drive Plasmodium falciparum antifolate resistance in Uganda.Nature communications · 2026Article
- Rational Exploration of 2,4-Diaminopyrimidines as DHFR Inhibitors Active againstJournal of medicinal chemistry · 2024Article
- Article
- Susceptibility of Ugandan Plasmodium falciparum Isolates to the Antimalarial Drug Pipeline.Microbiology spectrum · 2023Article
- Unveiling the Efficacy of Sesquiterpenes from Marine SpongeMolecules (Basel, Switzerland) · 2023Article
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Authors and funding
15 authors at 5 institutions in 3 countries.
Funding
Abstract
backgroundThe Plasmodium falciparum dihydrofolate reductase (PfDHFR) inhibitors pyrimethamine and cycloguanil (the active metabolite of proguanil) have important roles in malaria chemoprevention, but drug resistance challenges their efficacies. A new compound, P218, was designed to overcome resistance, but drug-susceptibility data for P falciparum field isolates are limited.
methodsWe studied ex vivo PfDHFR inhibitor susceptibilities of 559 isolates from Tororo and Busia districts, Uganda, from 2016 to 2020, sequenced 383 isolates, and assessed associations between genotypes and drug-susceptibility phenotypes.
resultsMedian half-maximal inhibitory concentrations (IC50s) were 42 100 nM for pyrimethamine, 1200 nM for cycloguanil, 13000 nM for proguanil, and 0.6 nM for P218. Among sequenced isolates, 3 PfDHFR mutations, 51I (100%), 59R (93.7%), and 108N (100%), were very common, as previously seen in Uganda, and another mutation, 164L (12.8%), had moderate prevalence. Increasing numbers of mutations were associated with decreasing susceptibility to pyrimethamine, cycloguanil, and P218, but not proguanil, which does not act directly against PfDHFR. Differences in P218 susceptibilities were modest, with median IC50s of 1.4 nM for parasites with mixed genotype at position 164 and 5.7 nM for pure quadruple mutant (51I/59R/108N/164L) parasites.
conclusionsResistance-mediating PfDHFR mutations were common in Ugandan isolates, but P218 retained excellent activity against mutant parasites.
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