Limited Geographical Origin and Global Spread of Sulfadoxine-Resistant dhps Alleles in Plasmodium falciparum Populations

Abstract

The infrequent selection of parasites highly resistant to sulfadoxine and the subsequent migration of resistant lineages from Asia to Africa are similar to the patterns observed in chloroquine and pyrimethamine resistance. These findings strongly suggest that the global migration of resistant parasites has played a decisive role in the establishment of drug-resistant P. falciparum parasites, and that similar patterns may be anticipated for the spread of artemisinin resistance.

Evolution of Plasmodium falciparum drug resistance: implications for the development and containment of artemisinin resistance

“…A large-scale study in Africa has shown that only five resistant lineages were observed in mild-to moderate-resistant parasites (parasites harboring one or two substitutions in DHPS) (69). Most recently, we have obtained evidence for the intercontinental spread of sulfadoxine resistance from Southeast Asia to East Africa (13). In that study, dhps alleles and linked microsatellite haplotypes were determined in sulfadoxine-resistant P. falciparum isolates obtained from Asia, the Pacific Islands, Africa, and South America.…”

“…Several recent studies on dhps alleles and microsatellite haplotypes closely linked to the dhps gene have revealed the putative geographical origins and spread of sulfadoxine-resistant P. falciparum isolates (11,13,38,40,68,69) (Fig. 5C).…”

“…As with DHFR, the extent of in vitro resistance to sulfadoxine is generally associated with the number of amino acid substitutions in DHPS (29,30,36). An Ala-to-Gly substitution at position 437 (encoding DHPS with amino acid sequences SGKAA at positions 436, 437, 540, 581, and 613, where the altered residue is underlined) has been proposed as the first step to sulfadoxine resistance (13,38,39). Triple-mutant DHPS enzymes (AGEAA, SGEGA, and SGNGA) demonstrate the highest levels of sulfadoxine resistance in the natural parasite populations, and parasites encoding quadruple-mutant DHPS enzymes have been detected (at rare frequencies) in some places in Southeast Asia (13,38,40).…”

“…Recent population geneticsbased analyses using microsatellite markers that flank drug-resistance genes have revealed that parasite lineages that are resistant to either chloroquine or pyrimethamine/sulfadoxine are of considerably limited geographic origin, suggesting that these resistant lineages subsequently were dispersed to many endemic areas (6)(7)(8)(9)(10)(11)(12)(13). Here, we review our recent understanding of the evolution of P. falciparum resistance to chloroquine and pyrimethamine/sulfadoxine, with special emphasis on the geographic epicenter of drug resistance, and consider the implications for the development and containment of artemisinin resistance.…”

Incomplete reversal of genotypic resistance of Plasmodium falciparum to chloroquine after a decade of change in malaria treatment policy in Uganda

“…Some patient samples had mixed Pfcrt-76K/T genotypes. A previous study by Mita et al 40 showed that patients with mixed infections had sensitive in vivo CQ response.…”