title: Geographic patterns of Plasmodium falciparum drug resistance distinguished by differential responses to amodiaquine and chloroquine.
abstract: Chloroquine (CQ) resistance (CQR) in Plasmodium falciparum originated from at least six foci in South America, Asia, and Oceania. Malaria parasites from these locations exhibit contrasting resistance phenotypes that are distinguished by point mutations and microsatellite polymorphisms in and near the CQR transporter gene, pfcrt, and the multidrug resistance transporter gene, pfmdr1. Amodiaquine (AQ), a 4-aminoquinoline related to CQ, is recommended and often used successfully against CQ-resistant P. falciparum in Africa, but it is largely ineffective across large regions of South America. The relationship of different pfcrt and pfmdr1 combinations to these drug-resistant phenotypes has been unclear. In two P. falciparum genetic crosses, particular pfcrt and pfmdr1 alleles from South America interact to yield greater levels of resistance to monodesethylamodiaquine (MDAQ; the active metabolite of AQ) than to CQ, whereas a pfcrt allele from Southeast Asia and Africa is linked to greater CQ than MDAQ resistance with all partner pfmdr1 alleles. These results, together with (i) available haplotype data from other parasites; (ii) evidence for an emerging focus of AQ resistance in Tanzania; and (iii) the persistence of 4-aminoquinoline-resistant parasites in South America, where CQ and AQ use is largely discontinued, suggest that different histories of drug use on the two continents have driven the selection of distinct suites of pfcrt and pfmdr1 mutations. Increasing use of AQ in Africa poses the threat of a selective sweep of highly AQ-resistant, CQ-resistant parasites with pfcrt and pfmdr1 mutations that are as advantaged and persistent as in South America.
authors.affiliation: Laboratory of Malaria and Vector Research and Biostatistics Research Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Juliana Martha
authors.initials: JM
authors.lastname: Sá
authors.forename: Olivia
authors.initials: O
authors.lastname: Twu
authors.forename: Karen
authors.initials: K
authors.lastname: Hayton
authors.forename: Sahily
authors.initials: S
authors.lastname: Reyes
authors.forename: Michael P
authors.initials: MP
authors.lastname: Fay
authors.forename: Pascal
authors.initials: P
authors.lastname: Ringwald
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Wellems
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000634:Aminoquinolines / Q000494:pharmacology; D000655:Amodiaquine / Q000494:pharmacology*; D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D002738:Chloroquine / Q000494:pharmacology*; D004351:Drug Resistance / Q000235:genetics*; D005843:Geography; D026901:Membrane Transport Proteins / Q000235:genetics; D009154:Mutation / Q000235:genetics; D010963:Plasmodium falciparum / Q000187:drug effects / Q000235:genetics*; D015800:Protozoan Proteins / Q000235:genetics; D040641:Quantitative Trait Loci; D012641:Selection, Genetic
chemical_list: D018528:ATP-Binding Cassette Transporters; D000634:Aminoquinolines; D000962:Antimalarials; D026901:Membrane Transport Proteins; C416369:PfCRT protein, Plasmodium falciparum; D015800:Protozoan Proteins; C059987:mdr gene protein, Plasmodium; D000655:Amodiaquine; D002738:Chloroquine; C001920:4-aminoquinoline