The pfmdr1 Gene Is Associated with a Multidrug-Resistant Phenotype in Plasmodium falciparumfrom the Western Border of Thailand
Price RN., Cassar C., Brockman A., Duraisingh M., van Vugt M., White NJ., Nosten F., Krishna S.
<jats:p>On the western border of Thailand, <jats:italic>Plasmodium falciparum</jats:italic> has become resistant to almost all antimalarial agents. The molecular basis of resistance in these parasite populations has not been well characterized. This study assessed genetic polymorphisms in the <jats:italic>pfmdr1</jats:italic> gene in 54 parasites collected from the western border of Thailand to determine the relationship of<jats:italic>pfmdr1</jats:italic> copy number and codon mutations with parasite sensitivities to mefloquine, chloroquine, halofantrine, quinine, and artesunate assessed in vitro. A point mutation at codon 86 (resulting in a change of Asn to Tyr) was associated with a significantly lower 50% inhibitory concentration (IC<jats:sub>50</jats:sub>) of mefloquine (median, 9 ng/ml versus 52.4 ng/ml; <jats:italic>P</jats:italic> = 0.003). Overall 35% of the isolates (19 of 54) had an increase in <jats:italic>pfmdr1</jats:italic> copy number, and all 19 carried the wild-type allele at codon 86. Increased<jats:italic>pfmdr1</jats:italic> copy number was associated with higher IC<jats:sub>50</jats:sub>s of mefloquine (<jats:italic>P</jats:italic> = 0.04) and artesunate (<jats:italic>P</jats:italic> = 0.005), independent of polymorphism at codon 86. The relationship between <jats:italic>pfmdr1</jats:italic> and resistance to structurally distinct antimalarial agents confirms the presence of a true multidrug-resistant phenotype.</jats:p>