Analysis of mefloquine resistance and amplification of pfmdr1 in multidrug-resistant Plasmodium falciparum isolates from Thailand.
Resistance to quinoline-containing compound has been associated with the Plasmodium falciparum multidrug resistance 1 (pfmdr1) gene. We analyzed wild P. falciparum isolates with high levels of chloroquine and mefloquine resistance for their macrorestriction maps of chromosome 5 and sequence of pfmdr1. Two types of chromosome 5 amplification were found. Eleven of 62 resistant isolates displayed Bgl 1 fragments larger than 100 kb. Twenty-nine isolates possessed multiple copies of the fragments. We failed to detect any amplification of this region on chromosome 5 in 22 mefloquine-resistant isolates, suggesting that other mechanisms can mediate the mefloquine-resistant phenotype. There was no direct association between pfmdr1 mutations and chloroquine sensitivity. Resistant lines could have Asn-86 and Tyr-184 or Phe-184, the predicted sequence of those chloroquine-sensitive isolates. No mutation at Asn-1042 and Asp-1246 was detected among these chloroquine-resistant isolates. Therefore, a few base substitutions in the pfmdr1 gene may not be sufficient to account for all chloroquine-resistant phenotypes.
Chaiyaroj
S C
SC
Department of Microbiology, Faculty of Science, Mahidol University, Bangkok, Thailand.
Buranakiti
A
A
Angkasekwinai
P
P
Looressuwan
S
S
Cowman
A F
AF
D000655:Amodiaquine / Q000494:pharmacology; D000818:Animals; D000962:Antimalarials / Q000494:pharmacology* / Q000627:therapeutic use; D002738:Chloroquine / Q000494:pharmacology; D002874:Chromosome Mapping; D017931:DNA Primers / Q000737:chemistry; D016054:DNA, Protozoan / Q000737:chemistry; D018432:Drug Resistance, Multiple / Q000235:genetics*; D004587:Electrophoresis, Agar Gel; D016521:Electrophoresis, Gel, Pulsed-Field; D006801:Humans; D020128:Inhibitory Concentration 50; D016778:Malaria, Falciparum / Q000188:drug therapy*; D015767:Mefloquine / Q000494:pharmacology* / Q000627:therapeutic use; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D011803:Quinine / Q000494:pharmacology; D012588:Scintillation Counting; D017422:Sequence Analysis, DNA; D013785:Thailand
D000962:Antimalarials; D017931:DNA Primers; D016054:DNA, Protozoan; D000655:Amodiaquine; D002738:Chloroquine; D011803:Quinine; D015767:Mefloquine