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

Abstract

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

Plasmodium falciparum dihydrofolate reductase alleles and pyrimethamine use in pregnant Ghanaian women.

“…The association between the DHFR gene alleles with the response to antifolates is less straightforward in vivo than in vitro possibly due to interfering factors such as pharmacokinetics and semi-immunity. [10][11][12][13][25][26][27][28][29][30] Nevertheless, in two recent studies, the triple DHFR gene mutation has been found to be reasonably predictive of the clinical failure of sulfadoxine-pyrimethamine treatment. 25,30 Both the Asn-108 and the Arg-59 variants were selected in women with either verified or reported pyrimethamine use.…”

Antimalarial Drug Resistance: Surveillance and Molecular Methods for National Malaria Control Programmes

“…No relation between clinical SP resistance and mutations in the DHFR gene could be established in a study carried out in Tanzania. Although all the isolates showed a point mutation in at least one codon of the DHFR gene, only 43% of the children had detectable parasitaemia seven days after treatment (Jelinek et al 1997).…”

Synthesis, in vitro and in vivo antimalarial assessment of sulfide, sulfone and vinyl amide-substituted 1,2,4-trioxanes prepared via thiol-olefin co-oxygenation (TOCO) of allylic alcohols

“…Room 2 ). This suggests that the cut off temperature at which the flipping begins is governed by the nature of the groups attached to the ring.…”

“…The cis-and trans-geometric isomers were assigned based on the coupling constants of the vinyl protons (J~13 and 16 Hz, respectively). Broadening of proton signals observed with the OCH 2 Further manipulation of the ester functionality of 63-73 was also attempted. The most important observation was that the vinyl esters readily undergo base-catalysed hydrolysis to the corresponding carboxylic acids (Scheme 7).…”

“…36 Based on this principle, a series 2 and SCH 2 , due to interconversion of different conformations of the six-membered endoperoxide ring system. As before, cooling to -20…”