title: Multiple transporters associated with malaria parasite responses to chloroquine and quinine.
abstract: Mutations and/or overexpression of various transporters are known to confer drug resistance in a variety of organisms. In the malaria parasite Plasmodium falciparum, a homologue of P-glycoprotein, PfMDR1, has been implicated in responses to chloroquine (CQ), quinine (QN) and other drugs, and a putative transporter, PfCRT, was recently demonstrated to be the key molecule in CQ resistance. However, other unknown molecules are probably involved, as different parasite clones carrying the same pfcrt and pfmdr1 alleles show a wide range of quantitative responses to CQ and QN. Such molecules may contribute to increasing incidences of QN treatment failure, the molecular basis of which is not understood. To identify additional genes involved in parasite CQ and QN responses, we assayed the in vitro susceptibilities of 97 culture-adapted cloned isolates to CQ and QN and searched for single nucleotide polymorphisms (SNPs) in DNA encoding 49 putative transporters (total 113 kb) and in 39 housekeeping genes that acted as negative controls. SNPs in 11 of the putative transporter genes, including pfcrt and pfmdr1, showed significant associations with decreased sensitivity to CQ and/or QN in P. falciparum. Significant linkage disequilibria within and between these genes were also detected, suggesting interactions among the transporter genes. This study provides specific leads for better understanding of complex drug resistances in malaria parasites.
authors.affiliation: Laboratory of Malaria and Vector Research, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Jianbing
authors.initials: J
authors.lastname: Mu
authors.forename: Michael T
authors.initials: MT
authors.lastname: Ferdig
authors.forename: Xiaorong
authors.initials: X
authors.lastname: Feng
authors.forename: Deirdre A
authors.initials: DA
authors.lastname: Joy
authors.forename: Junhui
authors.initials: J
authors.lastname: Duan
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Furuya
authors.forename: G
authors.initials: G
authors.lastname: Subramanian
authors.forename: L
authors.initials: L
authors.lastname: Aravind
authors.forename: Roland A
authors.initials: RA
authors.lastname: Cooper
authors.forename: John C
authors.initials: JC
authors.lastname: Wootton
authors.forename: Momiao
authors.initials: M
authors.lastname: Xiong
authors.forename: Xin-zhuan
authors.initials: XZ
authors.lastname: Su
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D002738:Chloroquine / Q000494:pharmacology*; D030561:Databases, Nucleic Acid; D004351:Drug Resistance / Q000502:physiology; D017125:Genes, Protozoan; D006801:Humans; D015810:Linkage Disequilibrium; D016778:Malaria, Falciparum; D026901:Membrane Transport Proteins / Q000235:genetics* / Q000378:metabolism; D008969:Molecular Sequence Data; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000235:genetics* / Q000378:metabolism; D011110:Polymorphism, Genetic; D015800:Protozoan Proteins / Q000235:genetics / Q000378:metabolism; D011803:Quinine / Q000494:pharmacology*
chemical_list: D000962:Antimalarials; D026901:Membrane Transport Proteins; D015800:Protozoan Proteins; D002738:Chloroquine; D011803:Quinine