Point Mutations in the Dihydrofolate Reductase and Dihydropteroate Synthase Genes of Plasmodium Falciparum and Resistance to Sulfadoxine-Pyrimethamine in Sri Lanka

Abstract

Sulfadoxine-pyrimethamine (SP) is the second-line treatment for Plasmodium falciparum malaria in Sri Lanka. Resistance to SP is caused by point mutations in the dihydrofolate reductase (Pf-dhfr) and dihydropteroate synthase (Pf-dhps) genes of P. falciparum. We determined the genotype of Pf-dhfr and Pf-dhps and the clinical response to SP in 30 field isolates of P. falciparum from Sri Lanka. All patients treated with SP had an adequate clinical response. Eighty-five percent (23 of 27) of pure field isolates carried parasites with double mutant alleles of Pf-dhfr (C59R + S108N) and showed about 200-fold higher levels of resistance to pyrimethamine than the wild type in a yeast system. None of the isolates had either known or novel mutations at other positions in the dhfr domain. In contrast, 67% (20 of 30) of the isolates carried parasites that were wild type for Pf-dhps. In Sri Lanka, detection of the triple mutant allele of Pf-dhfr will require tracking mutations at codon 51.

High prevalence of pfdhfr–pfdhps triple mutations associated with anti-malarial drugs resistance in Plasmodium falciparum isolates seven years after the adoption of sulfadoxine–pyrimethamine in combination with artesunate as first-line treatment in Iran

“…Nevertheless, with no clear reason, a sharp increase was observed in N 51 R 59 N 108 I 164 /S 436 G 437 haplotype from 2010 to 2014, which is the same as what was reported from Northeastern India (Mishra et al, 2014). The predominant pfdhfr haplotype in Iran seems to be N51,59R,108N rather than 51I,59R,108N similar to the previous reports from Afghanistan (Awab et al, 2013), Pakistan (Khatoon et al, 2009;Ghanchi et al, 2011;Kolaczinski et al, 2012), India (Biswas et al, 2000;Ahmed et al, 2004;Garg et al, 2009), Sri Lanka (Hapuarachchi et al, 2006), and Papua New Guinea (Mita et al, 2006). Therefore, mutation 51I might be a good molecular marker for rapid detection of triple mutant, showing pyrimethamine failure in Iran and its neighboring countries, Afghanistan and Pakistan.…”

Evaluation of prevalence's of pfdhfr and pfdhps mutations in Angola

“…The triple mutant 51 I 59 R 108 N (24,8%) was of low prevalence in the examined isolates, similarly to previous data reported in Sri Lanka [42] and Papua New Guinea [43], but different from the isolates from Malaysia [44], Brazil [45] and India [46] where this triple mutant was the predominant haplotype. In Africa, the Republic of Congo [28] and Gabon [29] also shows differences when compared with these Angolan data, except in the province of Cabinda.…”

Differences in selective pressure on dhps and dhfr drug resistant mutations in western Kenya

“…The results for dhps , in contrast to dhfr , revealed a greater proportion of wildtype alleles in the population. Similar data have been noted in previous studies, and Nzila et al [40] have suggested that after the triple mutant dhfr alleles spread sufficiently through a population, dhps mutant alleles increase in frequency due to selection by sulphadoxine [14,40,41]. While dhfr double mutants were predominantly present, triple mutants increased in frequency from 1992-1999, in accordance with positive selection for those mutants.…”