title: Role of Pfmdr1 in in vitro Plasmodium falciparum susceptibility to chloroquine, quinine, monodesethylamodiaquine, mefloquine, lumefantrine, and dihydroartemisinin.
abstract: The involvement of Pfmdr1 (Plasmodium falciparum multidrug resistance 1) polymorphisms in antimalarial drug resistance is still debated. Here, we evaluate the association between polymorphisms in Pfmdr1 (N86Y, Y184F, S1034C, N1042D, and D1246Y) and Pfcrt (K76T) and in vitro responses to chloroquine (CQ), mefloquine (MQ), lumefantrine (LMF), quinine (QN), monodesethylamodiaquine (MDAQ), and dihydroartemisinin (DHA) in 174 Plasmodium falciparum isolates from Dakar, Senegal. The Pfmdr1 86Y mutation was identified in 14.9% of the samples, and the 184F mutation was identified in 71.8% of the isolates. No 1034C, 1042N, or 1246Y mutations were detected. The Pfmdr1 86Y mutation was significantly associated with increased susceptibility to MDAQ (P = 0.0023), LMF (P = 0.0001), DHA (P = 0.0387), and MQ (P = 0.00002). The N86Y mutation was not associated with CQ (P = 0.214) or QN (P = 0.287) responses. The Pfmdr1 184F mutation was not associated with various susceptibility responses to the 6 antimalarial drugs (P = 0.168 for CQ, 0.778 for MDAQ, 0.324 for LMF, 0.961 for DHA, 0.084 for QN, and 0.298 for MQ). The Pfmdr1 86Y-Y184 haplotype was significantly associated with increased susceptibility to MDAQ (P = 0.0136), LMF (P = 0.0019), and MQ (P = 0.0001). The additional Pfmdr1 86Y mutation increased significantly the in vitro susceptibility to MDAQ (P < 0.0001), LMF (P < 0.0001), MQ (P < 0.0001), and QN (P = 0.0026) in wild-type Pfcrt K76 parasites. The additional Pfmdr1 86Y mutation significantly increased the in vitro susceptibility to CQ (P = 0.0179) in Pfcrt 76T CQ-resistant parasites.
authors.affiliation: Unité de Parasitologie, Département d'Infectiologie de Terrain, Institut de Recherche Biomédicale des Armées, Marseille, France Aix Marseille Université, Unité de Recherche sur les Maladies Infectieuses et Tropicales Emergentes, UM 63, CNRS 7278, IRD 198, Inserm 1095, Marseille, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Wurtz
authors.affiliation: Laboratoire d'Etude de la Chimiosensibilité du Paludisme, Fédération des Laboratoires, Hôpital Principal de Dakar, Dakar, Senegal.
authors.forename: Bécaye
authors.initials: B
authors.lastname: Fall
authors.affiliation: Unité de Parasitologie, Département d'Infectiologie de Terrain, Institut de Recherche Biomédicale des Armées, Marseille, France Aix Marseille Université, Unité de Recherche sur les Maladies Infectieuses et Tropicales Emergentes, UM 63, CNRS 7278, IRD 198, Inserm 1095, Marseille, France Centre National de Référence du Paludisme, Marseille, France.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Pascual
authors.affiliation: Service de Réanimation Médicale, Hôpital Principal de Dakar, Dakar, Senegal.
authors.forename: Mansour
authors.initials: M
authors.lastname: Fall
authors.affiliation: Unité de Parasitologie, Département d'Infectiologie de Terrain, Institut de Recherche Biomédicale des Armées, Marseille, France Aix Marseille Université, Unité de Recherche sur les Maladies Infectieuses et Tropicales Emergentes, UM 63, CNRS 7278, IRD 198, Inserm 1095, Marseille, France Laboratoire d'Etude de la Chimiosensibilité du Paludisme, Fédération des Laboratoires, Hôpital Principal de Dakar, Dakar, Senegal Centre National de Référence du Paludisme, Marseille, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Baret
authors.affiliation: Service des Urgences, Hôpital Principal de Dakar, Dakar, Senegal.
authors.forename: Cheikhou
authors.initials: C
authors.lastname: Camara
authors.affiliation: Service de Pédiatrie, Hôpital Principal de Dakar, Dakar, Senegal.
authors.forename: Aminata
authors.initials: A
authors.lastname: Nakoulima
authors.affiliation: Service de Réanimation Médicale, Hôpital Principal de Dakar, Dakar, Senegal.
authors.forename: Bakary
authors.initials: B
authors.lastname: Diatta
authors.affiliation: Service de Pathologie Infectieuse, Hôpital Principal de Dakar, Dakar, Senegal.
authors.forename: Khadidiatou Ba
authors.initials: KB
authors.lastname: Fall
authors.affiliation: Département de Médecine Interne et Spécialités Médicales de Pathologie Tropicale, Hôpital Principal de Dakar, Dakar, Senegal.
authors.forename: Pape Saliou
authors.initials: PS
authors.lastname: Mbaye
authors.affiliation: Laboratoire d'Etude de la Chimiosensibilité du Paludisme, Fédération des Laboratoires, Hôpital Principal de Dakar, Dakar, Senegal.
authors.forename: Yaya
authors.initials: Y
authors.lastname: Diémé
authors.affiliation: Laboratoire d'Etude de la Chimiosensibilité du Paludisme, Fédération des Laboratoires, Hôpital Principal de Dakar, Dakar, Senegal Laboratoire de Biologie, Institut Pasteur de Dakar, Dakar, Senegal.
authors.forename: Raymond
authors.initials: R
authors.lastname: Bercion
authors.affiliation: Chefferie, Hôpital Principal de Dakar, Dakar, Senegal.
authors.forename: Boubacar
authors.initials: B
authors.lastname: Wade
authors.affiliation: Unité de Parasitologie, Département d'Infectiologie de Terrain, Institut de Recherche Biomédicale des Armées, Marseille, France Aix Marseille Université, Unité de Recherche sur les Maladies Infectieuses et Tropicales Emergentes, UM 63, CNRS 7278, IRD 198, Inserm 1095, Marseille, France Laboratoire d'Etude de la Chimiosensibilité du Paludisme, Fédération des Laboratoires, Hôpital Principal de Dakar, Dakar, Senegal Centre National de Référence du Paludisme, Marseille, France Unité de Parasitologie et d'Entomologie, Département de Microbiologie, Institut de Recherche Biomédicale des Armées, Brétigny sur Orge, France bruno.pradines@free.fr.
authors.forename: Bruno
authors.initials: B
authors.lastname: Pradines
mesh_terms: D000328:Adult; D000655:Amodiaquine / Q000031:analogs & derivatives / Q000494:pharmacology; D000962:Antimalarials / Q000494:pharmacology*; D037621:Artemisinins / Q000494:pharmacology; D001692:Biological Transport; D002648:Child; D002738:Chloroquine / Q000494:pharmacology; D004351:Drug Resistance / Q000235:genetics*; D004912:Erythrocytes / Q000187:drug effects / Q000469:parasitology; D004983:Ethanolamines / Q000494:pharmacology; D005260:Female; D005449:Fluorenes / Q000494:pharmacology; D015870:Gene Expression; D006239:Haplotypes; D006801:Humans; D020128:Inhibitory Concentration 50; D000078102:Lumefantrine; D016778:Malaria, Falciparum / Q000188:drug therapy / Q000469:parasitology; D008297:Male; D015767:Mefloquine / Q000494:pharmacology; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics* / Q000378:metabolism; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000235:genetics* / Q000254:growth & development / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D011803:Quinine / Q000494:pharmacology; D012675:Senegal
chemical_list: D000655:Amodiaquine; D000962:Antimalarials; D037621:Artemisinins; D002738:Chloroquine; D004983:Ethanolamines; D005449:Fluorenes; D000078102:Lumefantrine; D015767:Mefloquine; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D011803:Quinine; C513498:Mdr1 protein, Plasmodium falciparum; C039060:artenimol; C047386:desethylamodiaquine