Low-grade sulfadoxine–pyrimethamine resistance in Plasmodium falciparum parasites from Lubango, Angola

Abstract

BackgroundMalaria is a major parasitic disease, affecting millions of people in endemic areas. Plasmodium falciparum parasites are responsible for the most severe cases and its resistance to anti-malarial drugs is notorious. This is a possible obstacle to the effectiveness of intermittent preventive treatment (IPT) based on sulfadoxine–pyrimethamine (SP) cures administrated to pregnant women (IPTp) during their pregnancy. As this intervention is recommended in Angola since 2006, it has assessed, in this country, the molecular profiles in P. falciparumdhfr and dhps, two polymorphic genes associated to pyrimethamine and sulfadoxine resistance, respectively.MethodsBlood samples from 52 falciparum patients were collected in Lubango, Angola and pfdhfr and pfdhps polymorphisms were analysed using nested-PCR and DNA sequencing.ResultsIn the pfdhfr gene, the 108N mutation was almost fixed (98 %), followed by 59R (63 %), 51I (46 %), 50R and 164L (2 %, respectively). No 16V/S mutations were found. The most common double mutant genotype was CNRN (59 + 108; 46 %), followed by CICN (51 + 108; 29 %) whereas IRN (51 + 59 + 108; 15 %), CNRNVL (59 + 108 + 164; 2 %) and RICN (50 + 51 + 108; 2 %) triple mutant genotypes were detected. Investigations of the pfdhps gene showed that the 437G mutation was the most prevalent (97 %). Only two and one samples disclosed the 540E (7 %) and the 436A (3 %), respectively. Single mutant SGKAA (437; 86 %) was higher than SGEAA (437 + 540; 7 %) or AGKAA (436 + 437; 3 %) double mutants genotypes. No polymorphism was detected at codons 581G and 613T/S. Combining pfdhfr and pfdhps alleles two triple mutant haplotypes (double mutant in dhfr and single mutant in dhps) were observed: the ACICNVI/SGKAA in 14 (56 %) samples and the ACNRNVI/SGKAA in five (20 %) samples. One quadruple mutant haplotype was detected (ACIRNVI/SGKAA) in six (24 %) P. falciparum samples. No quintuple pfdhfr–pfdhps mutant was noted.Conclusionpfdhfr and pfdhps gene mutations in isolates from Lubango are suggestive of a low-grade SP resistance and IPT for pregnant women and infant based on SP treatment could be effective. Routine molecular studies targeting polymorphism in these two genes need to be routinely conducted at country level.

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.…”

<p>Trends in Molecular Markers Associated with Resistance to Sulfadoxine-Pyrimethamine (SP) Among <em>Plasmodium falciparum</em> Isolates on Bioko Island, Equatorial Guinea: 2011–2017</p>

“…25 Pfdhfr and Pfdhps sequences from 20 other countries (18 for Pfdhps and 18 for Pfdhfr) were downloaded from NCBI or our previous study 26 to analyse global genetic diversity. [27][28][29][30][31][32][33][34][35][36]…”

Molecular Surveillance of Drug Resistance of Plasmodium falciparum Isolates Imported from Angola in Henan Province, China

“…The codons M74I, N75E, and K76T were the key points for the surveillance of CQR. The SNPs of the pfmdr1 gene were assumed to be associated with the efficacy of multiple antimalarial drugs (20,22). It was reported that the susceptibility of lumefantrine, mefloquine, and dihydroartemisinin could be increasing with the mutation of pfmdr1 86Y, while the resistance of CQ and amodiaquine were increasing (35).…”

“…The single nucleotide polymorphisms (SNPs) in pfdhfr and pfdhps were generally shown as multiple mutations. The common SNPs in pfdhfr were A16S, N51I, C59R, S108N, and I164L and in pfdhps were S436A, A437G, K540E, A581G, and A613S (22). Artemisinin resistance to P. falciparum first emerged in Cambodia (23,24), and the polymorphism of the Kelch 13 (K13) propeller domain in P. falciparum was considered a molecular marker of artemisinin resistance in 2014 (25).…”