ArticleAntimicrobial agents and chemotherapy2009
In vitro activity of antifolate and polymorphism in dihydrofolate reductase of Plasmodium falciparum isolates from the Kenyan coast: emergence of parasites with Ile-164-Leu mutation.
Article in Antimicrobial agents and chemotherapy, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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20 citing papers in PubMed, 46 citations in OpenAlex.
- A phase I trial to evaluate the safety and pharmacokinetics of low-dose methotrexate as an anti-malarial drug in Kenyan adult healthy volunteers.Malaria journal · 2011Trial
- Malaria and cancer: common features and interactions.Trends in parasitology · 2026Review
- Detection of low frequency artemisinin resistance mutations, C469Y, P553L and A675V, and fixed antifolate resistance mutations in asymptomatic primary school children in Kenya.BMC infectious diseases · 2025Article
- Targeted Amplicon Deep Sequencing for Monitoring Antimalarial Resistance Markers in Western Kenya.Antimicrobial agents and chemotherapy · 2022Article
- Decreased Susceptibility to Dihydrofolate Reductase Inhibitors Associated With Genetic Polymorphisms in Ugandan Plasmodium falciparum Isolates.The Journal of infectious diseases · 2022Article
- Article
- Screening of a library of traditional Chinese medicines to identify anti-malarial compounds and extracts.Malaria journal · 2018Article
- High prevalence of dihydrofolate reductase gene mutations in Plasmodium falciparum parasites among pregnant women in Nigeria after reported use of sulfadoxine-pyrimethamine.Pathogens and global health · 2018Article
- Article
- Temporal trends in prevalence of Plasmodium falciparum drug resistance alleles over two decades of changing antimalarial policy in coastal Kenya.International journal for parasitology. Drugs and drug resistance · 2014Article
- A genome wide association study of Plasmodium falciparum susceptibility to 22 antimalarial drugs in Kenya.PloS one · 2014Article
- Combination of probenecid-sulphadoxine-pyrimethamine for intermittent preventive treatment in pregnancy.Malaria journal · 2012Review
- Reduced impact of pyrimethamine drug pressure on Plasmodium malariae dihydrofolate reductase gene.Antimicrobial agents and chemotherapy · 2012Article
- In vitro susceptibility to pyrimethamine of DHFR I164L single mutant Plasmodium falciparum.Malaria journal · 2011Article
- Prevalence of Dihydrofolate reductase gene mutations in Plasmodium falciparum isolate from pregnant women in Nigeria.Infectious disease reports · 2011Review
- Molecular epidemiology of Plasmodium vivax anti-folate resistance in India.Malaria journal · 2011Article
- Methotrexate is highly potent against pyrimethamine-resistant Plasmodium vivax.The Journal of infectious diseases · 2011Article
- Vivax malaria: old drug, new uses?The Journal of infectious diseases · 2011Article
- Preclinical evaluation of the antifolate QN254, 5-chloro- N'6'-(2,5-dimethoxy-benzyl)-quinazoline-2,4,6-triamine, as an antimalarial drug candidate.Antimicrobial agents and chemotherapy · 2010Article
- Anticancer agents against malaria: time to revisit?Trends in parasitology · 2010Article
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Authors and funding
7 authors at 1 institution in 3 countries.
Funding
Abstract
We have analyzed the activities of the antifolates pyrimethamine (PM), chlorcycloguanil (CCG), WR99210, trimethoprim (TMP), methotrexate (MTX), and trimetrexate (TMX) against Kenyan Plasmodium falciparum isolates adapted in vitro for long-term culture. We have also assessed the relationship between these drug activities and mutations in dihydrofolate reductase (dhfr), a domain of the gene associated with antifolate resistance. As expected, WR99210 was the most potent drug, with a median 50% inhibitory concentration (IC50) of <0.075 nM, followed by TMX, with a median IC50 of 30 nM. The median IC50 of CCG was 37.80 nM, and that of MTX was 83.60 nM. PM and TMP were the least active drugs, with median IC50s of 733.26 nM and 29,656.04 nM, respectively. We analyzed parasite dhfr genotypes by the PCR-enzyme restriction technique. No wild-type dhfr parasite was found. Twenty-four of 33 parasites were triple mutants (mutations at codons 108, 51, and 59), and only 8/33 were double mutants (mutations at codons 108 and 51 or at codons 108 and 59). IC50s were 2.1-fold (PM) and 3.6-fold (TMP) higher in triple than in double mutants, though these differences were not statistically significant. Interestingly, we have identified a parasite harboring a mutation at codon 164 (Ile-164-Leu) in addition to mutations at codons 108, 51, and 59. This quadruple mutant parasite had the highest TMP IC50 and was in the upper 10th percentile against PM and CCG. We confirmed the presence of this mutation by sequencing. Thus, TMX and MTX are potent against P. falciparum, and quadruple mutants are now emerging in Africa.
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