Abstract
BackgroundSulfadoxine-pyrimethamine (SP) combination drug is currently being used in India for the treatment of Plasmodium falciparum as partner drug in artemisinin-based combination therapy (ACT). Resistance to sulfadoxine and pyrimethamine in P. falciparum is linked with mutations in dihydropteroate synthase (pfdhps) and dihydrofolate reductase (pfdhfr) genes respectively. This study was undertaken to estimate the prevalence of such mutations in pfdhfr and pfdhps genes in four states of India.MethodsPlasmodium falciparum isolates were collected from two states of India with high malaria incidence i.e., Jharkhand and Odisha and two states with low malaria incidence i.e., Andhra Pradesh and Uttar Pradesh between years 2006 to 2012. Part of sulfadoxine-pyrimethamine (SP) drug resistance genes, pfdhfr and pfdhps were PCR-amplified, sequenced and analyzed.ResultsA total of 217 confirmed P. falciparum isolates were sequenced for both Pfdhfr and pfdhps gene. Two pfdhfr mutations 59R and 108N were most common mutations prevalent in all localities in 77 % of isolates. Additionally, I164L was found in Odisha and Jharkhand only (4/70 and 8/84, respectively). Another mutation 51I was found in Odisha only (3/70). The pfdhps mutations 436A, 437G, 540E and 581G were found in Jharkhand and Odisha only in 13, 26, 14 and 13 % isolates respectively, and was absent in Uttar Pradesh and Andhra Pradesh. Combined together for pfdhps and pfdhfr locus, triple, quadruple, quintuple and sextuple mutations were present in Jharkhand and Odisha while absent in Uttar Pradesh and Andhra Pradesh.ConclusionWhile only double mutants of pfdhfr was present in low transmission area (Uttar Pradesh and Andhra Pradesh) with total absence of pfdhps mutants, up to sextuple mutations were present in high transmission areas (Odisha and Jharkhand) for both the genes combined. Presence of multiple mutations in pfdhfr and pfdhps genes linked to SP resistance in high transmission area may lead to fixation of multiple mutations in presence of high drug pressure and high recombination rate.Electronic supplementary materialThe online version of this article (doi:10.1186/s13071-015-1080-2) contains supplementary material, which is available to authorized users.
Highlights
Sulfadoxine-pyrimethamine (SP) combination drug is currently being used in India for the treatment of Plasmodium falciparum as partner drug in artemisinin-based combination therapy (ACT)
Mutation analysis of pfdhfr and pfdhps genes All 217 isolates were successfully sequenced for pfdhfr and pfdhps genes covering codon positions 16, 51, 59,108 and 164 of pfdhfr gene and codons 436, 437,540,581 and 613 of pfdhps gene
The distribution of amino acid substitution at various codon positions for pfdhfr and pfdhps genes are shown in Tables 2 and 3 respectively In total, sequencing results showed pure alleles at all the codons in n = 38 (17.51 %) isolates
Summary
Sulfadoxine-pyrimethamine (SP) combination drug is currently being used in India for the treatment of Plasmodium falciparum as partner drug in artemisinin-based combination therapy (ACT). One of the greatest challenges to malaria treatment is the development and spread of resistance in parasites especially in Plasmodium falciparum which threaten the usable lifespan of even artemisininbased combination therapies, affecting both the artemisinin component and the partner medicine [1]. A decade long use of artemisinin-based combination therapy (ACT) had been proved a hallmark anti-malarial therapy for all the malaria endemic countries [3]. Since 2013, prevalence of resistant genotype of falciparum against this partner drug SP, led to introduction of artemether-lumefantrine as antimalarial therapy for northeastern part of India [7, 8]
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