Molecular monitoring of dihydrofolatereductase (dhfr) and dihydropteroatesynthetase (dhps) associated with sulfadoxine-pyrimethamine resistance in Plasmodium vivax isolates of Palawan, Philippines

Acta Trop. 2018 Apr:180:81-87. doi: 10.1016/j.actatropica.2018.01.006. Epub 2018 Jan 17.

Abstract

The emergence of drug-resistant Plasmodium vivax poses problems for malaria control and elimination in some parts of the world, especially in developing countries where individuals are routinely exposed to the infection. The aim of this study was to determine the single nucleotide polymorphisms (SNPs) in dihydropteroate synthase (pvdhps) and dihydrofolate reductase (pvdhfr) genes associated with sulfadoxine-pyrimethamine (SP) drug resistance among P. vivax isolates collected in Palawan, Philippines. Genetic polymorphisms of pvdhps and pvdhfr were analysed by nested PCR. Analysis at specific codons I13P33F57S58T61S117I173 associated with pyrimethamine resistance in the pvdhfr gene revealed that most of the samples (66/87, 75.9%) carried double mutation at positions I13P33F57R58T61N117I173, while only 18.4% (16/87) of the isolates carried the wild-type haplotype (I13P33F57S58T61S117I173). For the pvdhps gene, the codons involved in sulfadoxine resistance S382A383K512A553V585 were investigated. Single mutation at position S382G383K512A553V585 was most observed in 68.0% (68/100) of the samples, whereas wild-type haplotype was found in 26.0% (26/100) of samples. The pvdhps and pvdhfr combination S382A383K512A553V585/I13P33F57S58T61S117I173 (wild-type), S382G383K512A553V585/I13P33F57R58T61N117I173, and S382A383K512A553V585-I13P33F57R58T61N117I173 were the most frequently observed combination haplotypes from the three study sites. The information on molecular markers associated with antifolate drug-resistance could help better understanding ofthe molecular epidemiology and situation of SP resistant P. vivax malaria in the country. Continuous surveillance of these genetic markers is necessary to monitor the evolution of SP resistance in the Philippines.

Keywords: Antifolate resistance; Plasmodium vivax; Sulfadoxine-pyrimethamine; pvdhfr; pvdhps.

MeSH terms

  • Antimalarials / pharmacology*
  • Dihydropteroate Synthase / genetics*
  • Drug Combinations
  • Drug Resistance / genetics*
  • Haplotypes
  • Humans
  • Malaria, Vivax / drug therapy
  • Molecular Epidemiology
  • Mutation
  • Philippines
  • Plasmodium vivax / drug effects*
  • Plasmodium vivax / genetics
  • Plasmodium vivax / isolation & purification
  • Polymerase Chain Reaction
  • Polymorphism, Single Nucleotide
  • Pyrimethamine / pharmacology*
  • Sulfadoxine / pharmacology*
  • Tetrahydrofolate Dehydrogenase / genetics*

Substances

  • Antimalarials
  • Drug Combinations
  • fanasil, pyrimethamine drug combination
  • Sulfadoxine
  • Tetrahydrofolate Dehydrogenase
  • Dihydropteroate Synthase
  • Pyrimethamine