title: Origin and dissemination of Plasmodium falciparum drug-resistance mutations in South America.
abstract: Multidrug resistance is a major obstacle to the control of Plasmodium falciparum malaria, and its origins and modes of dissemination are imperfectly understood. In this study, haplotyping and microsatellite analysis of malaria from 5 regions of the South American Amazon support the conclusion that the parasite mutations conferring mid- and high-level resistance to the antifolate combination sulfadoxine-pyrimethamine have a common origin. Parasites harboring these mutations are also found to share drug-resistance alleles that confer a unique chloroquine resistance phenotype and to be similar at loci not linked to drug resistance, although not genetically identical. Since the 1980s, multidrug-resistant P. falciparum has spread in a north-northwest manner across the continent, from an origin likely in the lower Amazon. This study highlights the importance of continent-wide malaria-control policies and suggests that the containment of resistance to the next generation of therapies may be feasible.
authors.affiliation: Malaria Section, Center for Vaccine Development, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.
authors.forename: Joseph F
authors.initials: JF
authors.lastname: Cortese
authors.forename: Alejandro
authors.initials: A
authors.lastname: Caraballo
authors.forename: Carmen E
authors.initials: CE
authors.lastname: Contreras
authors.forename: Christopher V
authors.initials: CV
authors.lastname: Plowe
mesh_terms: D000483:Alleles; D000595:Amino Acid Sequence; D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D002738:Chloroquine / Q000494:pharmacology; D003001:Cloning, Molecular; D018432:Drug Resistance, Multiple / Q000235:genetics; D005493:Folic Acid Antagonists / Q000494:pharmacology; D006239:Haplotypes; D006801:Humans; D016778:Malaria, Falciparum / Q000453:epidemiology / Q000469:parasitology*; D018895:Microsatellite Repeats; D008969:Molecular Sequence Data; D009097:Multienzyme Complexes / Q000235:genetics; D009154:Mutation; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D011739:Pyrimethamine / Q000494:pharmacology; D013020:South America / Q000453:epidemiology; D013413:Sulfadoxine / Q000494:pharmacology; D013762:Tetrahydrofolate Dehydrogenase / Q000235:genetics; D013940:Thymidylate Synthase / Q000235:genetics
chemical_list: C105176:6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase-7,8-dihydropteroate synthase; D000962:Antimalarials; D005493:Folic Acid Antagonists; D009097:Multienzyme Complexes; C056930:thymidylate synthase-dihydrofolate reductase; D013413:Sulfadoxine; D002738:Chloroquine; D013762:Tetrahydrofolate Dehydrogenase; D013940:Thymidylate Synthase; D011739:Pyrimethamine