title: Characterization of Plasmodium falciparum isolated from the Amazon region of Brazil: evidence for quinine resistance.
abstract: The prevalence and severity of drug-resistant malaria is emerging rapidly in the Amazon basin of Brazil. In support of clinical trials using the new antimalarial drug combination of atovaquone and proguanil, we performed in vitro drug sensitivities, molecular characterization of parasite populations using the circumsporozoite protein, merozoite surface antigen-1 (MSA-1), and MSA-2 markers, and an analysis of the Plasmodium falciparum multidrug resistance (pfmdr1) gene sequence and copy number in 26 isolates of P. falciparum obtained in a gold-mining endemic area in Peixoto de Azevedo, Mato Grosso State. All 26 isolates were found to be resistant to chloroquine (50% inhibitory concentration [IC50] = 100-620 nM) and sensitive to mefloquine (IC50 < 23 nM) and halofantrine (IC50 < 6 nM). The isolates also show reduced susceptibility to quinine (IC50 = 48-280 nM). Sequence analysis of the pfmdr1 gene revealed Asn, Phe, Cys, Asp, and Tyr in positions 86, 184, 1034, 1042, and 1246, respectively. These point mutations were similar to that previously described in other Brazilian isolates. Southern blot analysis revealed no amplification of the pfmdr1 gene. These results suggest that three different mechanisms for drug resistance exist for chloroquine, mefloquine, and quinine.
authors.affiliation: Instituto de Biofisica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Brazil.
authors.forename: M G
authors.initials: MG
authors.lastname: Zalis
authors.forename: L
authors.initials: L
authors.lastname: Pang
authors.forename: M S
authors.initials: MS
authors.lastname: Silveira
authors.forename: W K
authors.initials: WK
authors.lastname: Milhous
authors.forename: D F
authors.initials: DF
authors.lastname: Wirth
mesh_terms: D018528:ATP-Binding Cassette Transporters; D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D001938:Brazil / Q000453:epidemiology; D016054:DNA, Protozoan / Q000032:analysis*; D004351:Drug Resistance; D018432:Drug Resistance, Multiple / Q000235:genetics; D004359:Drug Therapy, Combination; D017125:Genes, Protozoan / Q000235:genetics; D006801:Humans; D016778:Malaria, Falciparum / Q000453:epidemiology / Q000378:metabolism; D015767:Mefloquine / Q000494:pharmacology; D010963:Plasmodium falciparum / Q000145:classification / Q000187:drug effects* / Q000302:isolation & purification; D017354:Point Mutation; D015800:Protozoan Proteins / Q000235:genetics*; D011803:Quinine / Q000494:pharmacology
chemical_list: D018528:ATP-Binding Cassette Transporters; D000962:Antimalarials; D016054:DNA, Protozoan; D015800:Protozoan Proteins; C059987:mdr gene protein, Plasmodium; D011803:Quinine; D015767:Mefloquine