title: Genetics of drug-resistant Plasmodium falciparum malaria in the Venezuelan state of Bolivar.
abstract: The state of Bolivar in Venezuela experiences episodic outbreaks of multidrug-resistant Plasmodium falciparum malaria. We obtained P. falciparum-infected blood samples in Bolivar in 1998-2000, and performed molecular assays for mutations conferring resistance to the antifolate combination of sulfadoxine-pyrimethamine (SP) and to chloroquine. All infections carried the dihydrofolate reductase (dhfr) S108A and N51I mutations, and 45% of the infections had the dhfr C50R mutation, which has been implicated in mid-level resistance to SP. Two dihydropteroate synthase (dhps) mutations also involved in SP resistance, A581G and K540E, were detected in 90% and 67% of the samples, respectively. The dhfr 1164L mutation, which confers high-level resistance, was not identified. The P. falciparum chloroquine resistance transporter (pfcrt) K76T mutation, which is critical for chloroquine resistance, was found in 167 of 168 infections. Six dhfr/dhps allelotypes and four pfcrt-resistant alleles were observed. Their interrelationships suggest a semi-clonal propagation of P. falciparum malaria in Bolivar, and an invasion of multi-resistant pathogens from Brazil. Despite national restrictions on the use of SP and chloroquine, genotypic resistance to these therapies remains widespread in Bolivar.
authors.affiliation: Immunology Institute, School of Medicine, Central University, Caracas, Venezuela. contrerc@camelot.rect.ucv.ve
authors.forename: Carmen E
authors.initials: CE
authors.lastname: Contreras
authors.forename: Joseph F
authors.initials: JF
authors.lastname: Cortese
authors.forename: Alejandro
authors.initials: A
authors.lastname: Caraballo
authors.forename: Christopher V
authors.initials: CV
authors.lastname: Plowe
mesh_terms: D000483:Alleles; D000818:Animals; D004094:Dihydropteroate Synthase / Q000235:genetics; D004351:Drug Resistance / Q000235:genetics; D006801:Humans; D016778:Malaria, Falciparum / Q000453:epidemiology / Q000469:parasitology*; D008565:Membrane Proteins / Q000235:genetics; D026901:Membrane Transport Proteins; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000235:genetics; D015800:Protozoan Proteins; D013762:Tetrahydrofolate Dehydrogenase / Q000235:genetics; D014687:Venezuela / Q000453:epidemiology
chemical_list: D008565:Membrane Proteins; D026901:Membrane Transport Proteins; C416369:PfCRT protein, Plasmodium falciparum; D015800:Protozoan Proteins; D013762:Tetrahydrofolate Dehydrogenase; D004094:Dihydropteroate Synthase