Mutational analysis of Plasmodium falciparum dihydrofolate reductase and dihydropteroate synthase genes in the interior division of Sabah, Malaysia

Abstract

BackgroundThe sulphadoxine/pyrimethamine (SDX/PYR) combination had been chosen to treat uncomplicated falciparum malaria in Malaysia for more than 30 years. Non-silent mutations in dihydrofolate reductase (dhfr) and dihydropteroate synthase (dhps) genes are responsible for the resistance to pyrimethamine and sulphadoxine, respectively. This study reports the mutational analysis of pfdhfr and pfdhps in single Plasmodium falciparum infection isolates from the interior division of Sabah, Malaysian Borneo.MethodsA total of 22 P. falciparum single infection isolates collected from two districts of the interior division of Sabah from February to November 2010 were recruited for the mutational study of pfdhfr and pfdhps. Both genes were amplified by nested PCR prior to DNA sequencing and mutational analysis.ResultsA total of three pfdhfr and four pfdhps alleles were identified. The most prevalent pfdhfr allele is ANRNL (86%) involving triple mutation at position 108(S to N), 59(C to R) and 164(I to L). In pfdhps, two novel alleles, SGTGA (73%) and AAKAA (5%) were identified. Alleles involving triple mutation in both pfdhfr (ANRNL) and pfdhps (SGTGA), which were absent in Sabah in a study conducted about 15 years ago, are now prevalent.ConclusionsHigh prevalence of mutations in SDX/PYR associated drug resistance genes are reported in this study. This mutational study of pfdhps and pfdhfr indicating that SDX/PYR should be discontinued in this region.

Prevalence of Plasmodium falciparum Molecular Markers of Antimalarial Drug Resistance in a Residual Malaria Focus Area in Sabah, Malaysia

“…falciparum CQ, PYR and SDX resistant previously reported in Pahang [9], Lundu, Sarawak [8] and Sabah: Kalabakan (Tawau Division) [6, 30], Keningau & Nabawan (Interior Division) [39], Kota Kinabalu (West Coast Division) [35], a Kota Marudu—present study, b Kudat [35] (Kudat Division). This map was generated by using SimpleMappr online software [40].…”

“…Triple mutation involving a combination of 1 mutant allele of pfdhps and 2 mutant alleles of pfdhfr (A437G/C59R/S108N) were predominant followed by low prevalence of quadruple (A437G/C59R/S108N/I164L) and quintuple (A437G/A581G/C59R/S108N/I164L) mutations combinations (Table 2). These combinations have also been observed in Keningau and Nabawan district in the interior of Sabah [41] and Kalabakan in the south-eastern coast of Sabah [30]. Although the prevalence of quadruple and quintuple combining mutations of pfdhps and pfdhfr were low, double mutations on pfdhfr alone have been associated with longer parasite clearance time and higher gametocytemia, the presence of gametocytes responsible for transmission [17].…”

“…Mutations on pfdhps and pfdhfr genes associated with SP resistance have been reported in most part of malaria endemic areas in Sabah and Sarawak (Fig 1 and Table 3) [5, 8, 41] and the neighbouring South Kalimantan, Indonesia [42]. Combination of triple pfdhfr mutation and double pfdhps mutation (quintuple mutant) have been associated with SP treatment failure [16].…”

Dihydrofolate-Reductase Mutations in Plasmodium knowlesi Appear Unrelated to Selective Drug Pressure from Putative Human-To-Human Transmission in Sabah, Malaysia

“…The accumulation of dhfr mutations associated with SP-resistance in P . falciparum over 30 years of SP usage is well documented in Sabah[ 31 , 68 , 69 ]. With P .…”

The prevalence of malaria and its therapeutic implication: A case study of Katcha Community

“…Sulphadoxine-pyrimethamine efficacy for acute malaria treatment has been compromised by resistance, but it retains partial activity among pregnant women with asymptomatic parasitaemia and might be useful (Gutman et al, 2015). High prevalence of mutations in sulphadoxine-pyrimethamine associated drug resistance genes have been reported indicating that it should be discontinued (Lau et al, 2013). Therefore, there is need for reinforced surveillance of drug efficacy (Zatra et al, 2012).…”