Do mutations in Plasmodium falciparum dihydropteroate synthase and dihydrofolate reductase confer resistance to sulfadoxine-pyrimethamine in Iran?

Abstract

The key codons of dihydropteroate synthase (dhps) and dihydrofolate reductase (dhfr) genes implicated in sulfadoxine-pyrimethamine (SP) resistance were determined by allele-specific polymerase chain reaction in Plasmodium falciparum isolates collected in 1999 from 35 Iranian patients treated with SP. Seven isolates had Glu-540 dhps allele but 5 of these isolates were characterized to possess wild-type dhfr alleles. Seven additional isolates were polyclonal with mixed Lys- and Glu-540. The key dhfr mutation associated with pyrimethamine resistance, Asn-108, was found in 4 isolates. In one patient the presence of Lys- and Glu-540 in dhps and Asn-108 and Arg-59 in dhfr was associated with treatment failure. However, more studies are needed to determine whether clinical response to SP and mutations in these genes are correlated in Iran.

Sulfadoxine Resistance in Plasmodium vivax Is Associated with a Specific Amino Acid in Dihydropteroate Synthase at the Putative Sulfadoxine-Binding Site

“…It should be noted here that the K540E mutation is not predicted to cause treatment failure when found independent of other mutations. The K540E mutation is primarily found in combination with up to 5 additional mutations in DHPS and dihydrofolate reductase (4,12,15,24). It is most likely that K540E correlates well with treatment failure due to its combination with other mutations in these genes.…”

Genetic diversity in merozoite surface protein (MSP)-1 and MSP-2 genes of Plasmodium falciparum in a major endemic region of Iran

“…The tribulations encountered in Sistan and Baluchistan Provinces, Iran, are resistance of P. falciparum to drugs (Edrissian et al, 1993;Eskandarian et al, 2002;Jafari et al, 2003), and that of vectors to insecticides, likewise importation of malaria mostly of P. falciparum originating from Afghani and to some lesser extent, from Pakistani immigrants. Hence, designing efficient malaria vaccine is useful for control of falciparum malaria in this area.…”

Evolution of Resistance to Sulfadoxine-Pyrimethamine in Plasmodium falciparum

“…High levels of resistance to chloroquine have forced some countries to switch their first-line drug to sulfadoxine-pyrimethamine (SP, trade name Fansidar). However, resistance to this drug combination is developing fast, with treatment failure being reported in Africa, Asia, Indonesia, and South America (5,7,16,20,31).Pyrimethamine and sulfadoxine act synergistically to inhibit two enzymes important in the parasite's folate biosynthetic pathway, dihydrofolate reductase (DHFR) and dihydropteroate synthetase (DHPS) (13). Point mutations in the DHFR and DHPS genes confer resistance to pyrimethamine and sulfadoxine, respectively, with decreasing in vitro Plasmodium falciparum susceptibility related to the number of mutations in each gene (6,30,34).…”

“…High levels of resistance to chloroquine have forced some countries to switch their first-line drug to sulfadoxine-pyrimethamine (SP, trade name Fansidar). However, resistance to this drug combination is developing fast, with treatment failure being reported in Africa, Asia, Indonesia, and South America (5,7,16,20,31).…”

“…Point mutations in the DHFR and DHPS genes confer resistance to pyrimethamine and sulfadoxine, respectively, with decreasing in vitro Plasmodium falciparum susceptibility related to the number of mutations in each gene (6,30,34). The same mutations have been linked to treatment failure in the clinical setting (5,7,20,33); the presence of mutations in DHFR appear to be more important in causing treatment failure than DHPS mutations (5). Although the molecular basis for SP resistance is understood, the factors promoting the development and transmission of these mutants are less clear.…”