Origins and spread of novel genetic variants of sulfadoxine–pyrimethamine resistance in Plasmodium falciparum isolates in Indonesia

Abstract

BackgroundWhile malaria incidence in Indonesia has decreased threefold in the last decade, more than 200,000 cases were reported in 2016. Different endemicity of Plasmodium falciparum malaria among several islands in Indonesia has been recognized and two unique mutations of P. falciparum dihydropteroate synthase (pfdhps) affecting sulfadoxine–pyrimethamine (SP) resistance were detected from the research of SP efficiency and genotype analysis in South Kalimantan. In this study, geographical distribution and origin of these pfdhps K540T and I588F mutations were analysed.MethodsMalaria parasites DNA from several endemic areas in Indonesia; Sumatera, Java, Kalimantan, Lombok, Sumbawa, Timor, Sulawesi, and Papua islands; in two periods, 2004–2006 and 2009–2012 were subjected for pfdhfr and pfdhps sequence analysis.ResultsDifferent genotype polymorphisms of pfdhfr and pfdhps were observed in the parasites from various regions in Indonesia and relatively more divergent genotypes were determined from Kalimantan isolates in both 2004–2006 and 2009–2012. The parasites containing K540T mutation were identified in 2004–2006 isolates from East Kalimantan, East Java and Sumbawa as an SGTGA haplotype. The other I588F mutation was also determined in 2004–2006 parasites, isolated from Lombok and Sumbawa islands as an SGEAA(588F) haplotype. The parasites with pfdhfr/pfdhps quintuple or sextuple mutation, a genotype marker of SP resistance, were determined mostly in Kalimantan in both 2004–2006 and 2009–2012.ConclusionAnalysis of the prevalence and pfdhfr/pfdhps combined genotypes of K540T or I588F mutations suggested that K540T might be origin in Kalimantan Island and I588F in Sumbawa Island and then these were spread to other areas along with people movement. This research indicates regular monitoring of drug efficacy and parasite genotype analysis is important to keep efficiency and prevent the spread of resistance. It is also essential for the latest anti-malarial drug artemisinin-based combination therapy.

High multiple mutations of Plasmodium falciparum-resistant genotypes to sulphadoxine-pyrimethamine in Lagos, Nigeria

“…Moderate level of resistance conferred by dhfr and dhps polymorphisms is typically found in West Africa with the absence of I164L polymorphism that is associated with very high-level SP resistance (up to 20 000-fold decrease in susceptibility in comparison with the wild type) [50]. I164L polymorphism have been variously reported in parts of East Africa [51], some parts of South Africa [52] and Asia [53]. There is dearth of information on why I164L mutation does not occur in Africa despite extensive drug pressure.…”

Single Nucleotide Polymorphisms of Pfdhfr and Pfdhps Genes: Implications for Malaria Prophylactic Strategies in Maiduguri, Northeast Nigeria

“…e present study reports the prevalence of Pfdhfr SNPs at codons N51I, C59R, and S108N and codons S436A/F, A437G, and K540E of Pfdhps and discusses the implications on malaria prophylactic strategies in Maiduguri, Northeast Nigeria. Pfdhfr and Pfdhps genes have been widely used as biomarkers for monitoring pyrimethamine and sulfadoxine resistance, respectively [23,24,26,27,36]. e detection of Pfdhfr mutations in the present study is an indication of circulating pyrimethamine-resistant P. falciparum strains in the region.…”

“…Previous studies have reported SP resistance in Nigeria [20][21][22] and other countries where strategies are deployed [23][24][25][26]; thus, the need for periodic monitoring of SP efficacy to ensure early detection of drug resistance. Single nucleotide polymorphisms (SNPs) in P. falciparum dihydrofolate reductase (Pfdhfr) and P. falciparum dihydropteroate synthase (Pfdhps) are strong predictors of SP resistance [20,23,26,27]. Pyrimethamine resistance is associated with point mutations at codons N51I, C59R, S108N, and I164L of Pfdhfr [28], while sulfadoxine resistance is associated with point mutations at codons S436A/F, A437G, K540E, A581G, and A613S/T of Pfdhps [29].…”

In-vivo Antiplasmodial Activity of Sulfadoxine/Pyrimethamine/Doxycycline on Plasmodium berghei Infected Mice

“…S/P is also used in combination with amodiaquine for malaria chemoprevention [8]. However, there is emergence and wide spread resistant to S/P by Plasmodium parasites primarily P. falciparum [9]. This resistance has been attributed to point mutations in its target enzymes (dihydropteroate synthase and dihydrofolate reductase) which are involved in folate biosynthesis pathway [10].…”