Mutations in the pfmdr1, DHFR and DHPS Genes of Plasmodium Falciparum Are Associated With In-Vivo Drug Resistance in West Papua, Indonesia

Trans R Soc Trop Med Hyg. Jan-Feb 2001;95(1):43-9. doi: 10.1016/s0035-9203(01)90329-3.

Abstract

This study (conducted in 1996-99) examines the association of mutations in pfmdr1, dihydrofolate reductase (dhfr) and dihydropteroate synthase (dhps) genes of Plasmodium falciparum with in-vivo drug resistance in West Papua, Indonesia. Initially, 85 patients infected with P. falciparum were treated with chloroquine, of whom 21 were cleared of parasites, 49 had parasitaemias classified as RI, RII or RIII resistance and 1 patient had recrudescent parasitaemia. Fansidar (pyrimethamine-sulfadoxine) was the second-line treatment and 18 patients were cleared of parasites and 31 had continuing infections classified as RI, RII or RIII resistance and 1 patient had recrudescent parasitaemia. The pfmdr1, dhfr and dhps genes were examined for mutations previously shown to be associated with resistance to these drugs. In this study, mutations in pfmdr1 were associated with chloroquine resistance and mutations in both dhfr and dhps were associated with Fansidar resistance in vivo. Interestingly, Gly-437 in dhps along with Arg-59/Asn-108 in dhfr were associated with RI, RII and RIII resistance whereas Glu-540 was highly associated with only RII and RIII Fansidar resistance. This finding supports the hypothesis that the molecular basis of RI, RII and RIII Fansidar resistance involves an accumulation of mutations in both dhfr and dhps. These results suggest that mutations in both dhfr and dhps genes are a good predictor of potential Fansidar treatment failure.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP-Binding Cassette Transporters*
  • Animals
  • Antimalarials / therapeutic use
  • Dihydropteroate Synthase / genetics*
  • Drug Combinations
  • Drug Resistance, Microbial
  • Indonesia / epidemiology
  • Malaria, Falciparum / drug therapy
  • Malaria, Falciparum / epidemiology
  • Malaria, Falciparum / genetics
  • Mutation / genetics*
  • Plasmodium falciparum / genetics*
  • Polymerase Chain Reaction / methods
  • Polymorphism, Restriction Fragment Length
  • Protozoan Proteins / genetics*
  • Pyrimethamine / therapeutic use
  • Sulfadoxine / therapeutic use
  • Tetrahydrofolate Dehydrogenase / genetics

Substances

  • ATP-Binding Cassette Transporters
  • Antimalarials
  • Drug Combinations
  • Protozoan Proteins
  • mdr gene protein, Plasmodium
  • fanasil, pyrimethamine drug combination
  • Sulfadoxine
  • Tetrahydrofolate Dehydrogenase
  • Dihydropteroate Synthase
  • Pyrimethamine