Pyrimethamine resistant mutations in Plasmodium falciparum

Thaithong, Sodsri; Chan, Shiu-Wan; Songsomboon, Supasorn; Wilairat, Prapon; Seesod, Nowarat; Sueblinwong, T.; Goman, Michael; Ridley, Robert G.; Beale, G. H.

doi:10.1016/0166-6851(92)90047-n

Cited by 69 publications

(36 citation statements)

References 24 publications

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“…Therefore various studies concerning the determination of genetic changes as the basis of clinical resistance have been conducted. Mutations in various codons of the DHFR gene have been linked successfully to in vitro resistance in various laboratory clones and occasional field isolates (Cowman et al 1988;Peterson et al 1988;Snewin et al 1989;Zolg et al 1989;Thaithong et al 1992;Basco et al 1995;Reeder et al 1996). The determination of mutations at codon 108 of the DHFR gene has been used previously to estimate the amount of parasite resistance against pyrimethamine in West Africa and this method has been proposed for surveillance purposes (Plowe et al 1995).…”

Section: Discussionmentioning

confidence: 99%

High prevalence of mutations in the dihydrofolate reductase gene of Plasmodium falciparum in isolates from Tanzania without evidence of an association to clinical sulfadoxine/pyrimethamine resistance

Jelı́nek

Rønn

Curtis

et al. 1997

Tropical Med Int Health

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SummaryRecently the efficacy of sulfadoxine/pyrimethamine (S/P) in treatment of uncomplicated falciparum malaria in Tanzania has been seriously compromised by the development of resistance. The occurrence of active site mutations in the Plasmodium falciparum gene sequence coding for dihydrofolate reductase (DHFR) is known to confer resistance to pyrimethamine. This study investigates the occurrence of these mutations in infected blood samples taken from Tanzanian children before treatment with S/P and their relationship to parasite breakthrough by day 7. The results confirm the occurrence of one or more DHFR mutations in all the samples, but no relationship was found with the presence of parasites in the blood at day 7. The results suggest that alterations in the coding region for dihydropteroate synthetase (DHPS), the enzyme target for sulfadoxine, should be studied in order to predict resistance to the S/P combination. It has been proposed earlier that sulfadoxine could itself act on DHFR, because of a false dihydrofolate produced by drug metabolism through DHPS and dihydrofolate synthase. The results of this treatment study suggest that such a possibility is unlikely.keywords Plasmodium falciparum, Tanzania, sulfadoxine/pyrimethamine resistance correspondence Dr

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Section: Discussionmentioning

confidence: 99%

High prevalence of mutations in the dihydrofolate reductase gene of Plasmodium falciparum in isolates from Tanzania without evidence of an association to clinical sulfadoxine/pyrimethamine resistance

Jelı́nek

Rønn

Curtis

et al. 1997

Tropical Med Int Health

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“…Previous studies have demonstrated that a change from Ile to Leu at position 164, coupled with Asn-108 plus Ile-51 and/or Arg-59 confers high-level resistance to both pyrimethamine and cycloguanil. [3][4][5][6][7][8] New mutations in the DHFR gene at position 50 (Cys to Arg) and a five amino acid repetitive insert between positions 30 and 31 have been found to be highly prevalent in Bolivia, where SP resistance is high. 9,10 Recently, a novel leucine mutation at position 140 in the DHFR gene was found in the isolate VP8, which also has the characteristic changes at positions Val-16 and Thr-108, which confer cycloguanil resistance.…”

mentioning

confidence: 99%

Point mutations in dihydrofolate reductase and dihydropteroate synthase genes of Plasmodium falciparum isolates from Venezuela.

Urdaneta¹,

Plowe²,

Goldman³

et al. 1999

Am J Trop Med Hyg

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Abstract. The present study was designed to characterize mutations in dihydrofolate reductase (DHFR) and dihydropteroate synthase (DHPS) genes of Plasmodium falciparum in the Bolivar region of Venezuela, where high levels of clinical resistance to sulfadoxine-pyrimethamine (SP, Fansidar; F. Hoffman-La Roche, Basel, Switzerland) has been documented. We used a nested mutation-specific polymerase chain reaction and restriction digestion methods to measure 1) the prevalence of DHFR mutations at 16, 50, 51, 59, 108, and 164 codon positions, and 2) the prevalence of mutations in the 436, 437, 581, and 613 codon sites in DHPS gene. In the case of the DHFR gene, of the 54 parasite isolates analyzed, we detected the presence of Asn-108 and Ile-51 in 96% of the isolates and Arg-50 mutation in 64% of the isolates. Each of these mutations has been associated with high level of resistance to pyrimethamine. Only 2 samples (4%) showed the wild type Ser-108 mutation and none showed Thr-108 and Val-16 mutations that are specific for resistance to cycloguanil. In the case of DHPS gene, we found a mutation at position 437 (Gly) in 100% of the isolates and Gly-581 in 96% of the isolates. The simultaneous presence of mutations Asn-108 and Ile-51 in the DHFR gene and Gly-437 and Gly-581 in the DHPS gene in 96% of the samples tested suggested that a cumulative effect of mutations could be the major mechanism conferring high SP resistance in this area.

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“…Briefly, parasites were grown in RPMI1640 medium (supplemented with 37.5 mM HEPES, 7 mM D-glucose, 6 mM NaOH, 25 毺 g/mL gentamicin sulphate, 2 mM L-glutamine and 10 % human serum) under an atmosphere of 96 % nitrogen, 3 % carbon dioxide, and 1 % oxygen. Synchronization of the parasite to early ring stage was performed using 5 % sorbitol.…”

Section: Parasite Culturementioning

confidence: 99%

“…The P. falciparum clone T9/94 used in this study was cultured in vitro in group O human red blood cells according to the previously described method [6] . Briefly, parasites were grown in RPMI1640 medium (supplemented with 37.5 mM HEPES, 7 mM D-glucose, 6 mM NaOH, 25 毺 g/mL gentamicin sulphate, 2 mM L-glutamine and 10 % human serum) under an atmosphere of 96 % nitrogen, 3 % carbon dioxide, and 1 % oxygen.…”

Section: Parasite Culturementioning

confidence: 99%

“…Resistance to antifolates occurs through stepwise mutations of this enzyme, which eventually causes the change in parasite's sensitivity to the drugs [4,5] . To understand the underlying mechanism of antifolate resistance, Thaithong et al [6] obtained the mutant clone T9/94-M1-1(b3) with increased resistance to pyrimethamine through selective drug pressure. The mutant clone T9/94-M1-1(b3) exhibited a 100 fold increase in minimal inhibitory concentration (MIC) of pyrimethamine (5 暳 10 -6 M) as compared with the original parent clone (5 暳 10 -8 M).…”

Section: Introductionmentioning

confidence: 99%

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Comparison of protein patterns between Plasmodium falciparum mutant clone T9/94-M1-1(b3) induced by pyrimethamine and the original parent clone T9/94

Rungsihirunrat

Chai่jaroenkul

Siripoon

et al. 2012

Asian Pacific Journal of Tropical Biomedicine

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Pyrimethamine resistant mutations in Plasmodium falciparum

Cited by 69 publications

References 24 publications

High prevalence of mutations in the dihydrofolate reductase gene of Plasmodium falciparum in isolates from Tanzania without evidence of an association to clinical sulfadoxine/pyrimethamine resistance

High prevalence of mutations in the dihydrofolate reductase gene of Plasmodium falciparum in isolates from Tanzania without evidence of an association to clinical sulfadoxine/pyrimethamine resistance

Point mutations in dihydrofolate reductase and dihydropteroate synthase genes of Plasmodium falciparum isolates from Venezuela.

Comparison of protein patterns between Plasmodium falciparum mutant clone T9/94-M1-1(b3) induced by pyrimethamine and the original parent clone T9/94

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