Discordant Temporal Evolution of Pfcrt and Pfmdr1 Genotypes and Plasmodium falciparum In Vitro Drug Susceptibility to

Analysis of the evolution of drug target genes under changing drug policy is needed to assist monitoring of Plasmodium falcipa-rum drug resistance in the field. Here we genotype Pfcrt and Pfdmr1 of 700 isolates collected in French Guiana from 2000 (5 years after withdrawal of chloroquine) to 2008, i.e., the period when the artemether-lumefantrine combination was progressively in-troduced andmefloquine was abandoned. Gene sequencing showed fixation of the 7G8-type Pfcrt SMVNT resistance haplotype and near fixation of the NYCDY Pfdmr1 haplotype. Pfdmr1 gene copy number correlated with 50 % inhibitory concentrations of mefloquine and halofantrine (r 0.64 and 0.47, respectively, n 547); its temporal changes paralleled changes in in vitromeflo-quine susceptibility. However, the molecular parameters studied did not account for the regained in vitro susceptibility to chlo-roquine and showed a poor correlation with susceptibility to artemether, lumefantrine, or quinine. Identification of novel mark-ers of resistance to these antimalarials is needed in this South American area. Plasmodium falciparum drug resistance is a major concern formalaria control. Mutations of the P. falciparum chloroquine resistance transporter (Pfcrt), a member of the drug metabolite transporter superfamily, have been identified as causal determi-nants of chloroquine resistance in vitro (17, 41) and associated with chloroquine treatment failures (13). Susceptibility to meflo-quine is associated with single nucleotide polymorphisms (SNPs