Surveillance of antifolate-resistant malaria

Abstract

The epidemiology of antifolate resistance in Plasmodium falciparum can be monitored by molecular techniques due to a high correlation between mutations in dihydrofolate reductase (DHFR) and dihydropteroate synthase (DHPS) and in-vitro resistance to pyrimethamine and sulphadoxine.1Basco LK Eldin de Pécoulas P Wilson CM Le Bras J Mazabraud A Point mutations in the dihydrofolate reductase-thymidylate synthase gene and pyrimethamine and cycloguanil resistance in Plasmodium falciparum.Mol Biochem Parasitol. 1995; 69: 135-138Crossref PubMed Scopus (163) Google Scholar, 2Wang P Read M Sims PFG Hyde JE Sulfadoxine resistance in the human malaria parasite Plasmodium falciparum is determined by mutations in dihydropteroate synthetase and an additional factor associated with folate utilization.Mol Microbiol. 1997; 23: 979-986Crossref PubMed Scopus (242) Google Scholar The results of James Kublin and colleagues (May 30, p 1629)3Kublin JG Witzig RS Shankar AH et al.Molecular assays for surveillance of antifolate-resistant malaria.Lancet. 1998; 351: 1629-1630Summary Full Text Full Text PDF PubMed Scopus (81) Google Scholar and other studies4Basco LK, Tahar R, Ringwald P. Molecular basis of in vivo resistance to sulfadoxine-pyrimethamine in African adult patients infected with Plasmodium falciparum malaria parasites. Antimicrob Agents Chemother (in press).Google Scholar, 5Wang P Lee CS Bayoumi R et al.Resistance to antifolates in Plasmodium falciparum monitored by sequence analysis of dihydropteroate synthetase and dihydrofolate reductase alleles in a large number of field samples of diverse origins.Mol Biochem Parasitol. 1997; 89: 161-177Crossref PubMed Scopus (206) Google Scholar reinforce the association between the genotype and phenotype.3Kublin JG Witzig RS Shankar AH et al.Molecular assays for surveillance of antifolate-resistant malaria.Lancet. 1998; 351: 1629-1630Summary Full Text Full Text PDF PubMed Scopus (81) Google Scholar, 4Basco LK, Tahar R, Ringwald P. Molecular basis of in vivo resistance to sulfadoxine-pyrimethamine in African adult patients infected with Plasmodium falciparum malaria parasites. Antimicrob Agents Chemother (in press).Google Scholar, 5Wang P Lee CS Bayoumi R et al.Resistance to antifolates in Plasmodium falciparum monitored by sequence analysis of dihydropteroate synthetase and dihydrofolate reductase alleles in a large number of field samples of diverse origins.Mol Biochem Parasitol. 1997; 89: 161-177Crossref PubMed Scopus (206) Google Scholar The findings of Kublin and his colleagues in the Amazonian basin are not, however, representative and differ from the mutational patterns observed in Africa. In their series, all 11 patients with sensitive response were infected with P falciparum isolates that carry a wild-type DHPS and a mutant Asn-108 allele in DHFR. In Africa, sensitive response was reported with parasites that carry a wild-type DHPS and a wild-type or mutant (Asn-108 with or without Arg-59) DHFR.4Basco LK, Tahar R, Ringwald P. Molecular basis of in vivo resistance to sulfadoxine-pyrimethamine in African adult patients infected with Plasmodium falciparum malaria parasites. Antimicrob Agents Chemother (in press).Google Scholar In the Amazon, there was no difference in the genotype in relation to the level of in-vivo resistance to sulphadoxine-pyrimethamine. In Africa, we found a tendency towards a higher level of in-vivo resistance in the presence of triple mutations in DHFR (Ile-51, Arg-59, and Asn-108).4Basco LK, Tahar R, Ringwald P. Molecular basis of in vivo resistance to sulfadoxine-pyrimethamine in African adult patients infected with Plasmodium falciparum malaria parasites. Antimicrob Agents Chemother (in press).Google Scholar DHFR mutant codons 30 and 164 and DHPS mutant codon 540, frequently detected in the Amazon, are rare in Africa. By contrast, the mutant DHFR codon Arg-59 is common in Africa but not in the Amazon. These genotype differences may reflect independent genetic changes in malaria parasites from different geographical origins. Before molecular analysis is used to describe the epidemiology of antifolate resistance in an endemic area, further studies that correlate the in-vivo resistance and point mutations are needed to characterise the genotype of drug-sensitive and drug-resistant parasites.