title: Deciphering the Resistance-Counteracting Functions of Ferroquine in Plasmodium falciparum-Infected Erythrocytes.
abstract: The aminoquinoline chloroquine (CQ) has been widely used for treating malaria since World War II. Resistance to CQ began to spread around 1957 and is now found in all malarious areas of the world. CQ resistance is caused by multiple mutations in the Plasmodium falciparum chloroquine resistance transporter (PfCRT). These mutations result in an increased efflux of CQ from the acidic digestive vacuole (DV) to the cytosol of the parasite. This year, we proposed a strategy to locate and quantify the aminoquinolines in situ within infected red blood cells (iRBCs) using synchrotron based X-ray nanoprobe fluorescence. Direct measurements of unlabeled CQ and ferroquine (FQ) (a ferrocene-CQ conjugate, extremely active against CQ-resistant strains) enabled us to evidence fundamentally different transport mechanisms from the cytosol to the DV between CQ and FQ in the CQ-susceptible strain HB3. These results inspired the present study of the localization of CQ and FQ in the CQ-resistant strain W2. The introduction of the ferrocene core in the lateral side chain of CQ has an important consequence: the transporter is unable to efflux FQ from the DV. We also found that resistant parasites treated by FQ accumulate a sulfur-containing compound, credibly glutathion, in their DV.
authors.affiliation: Université Lille 1 , UCCS, CNRS UMR 8181, 59652 Villeneuve d'Ascq Cedex, France.
authors.forename: Faustine
authors.initials: F
authors.lastname: Dubar
authors.affiliation: Inserm, U836, équipe 6, Grenoble Institut des Neurosciences , 38054 Grenoble, France ; ESRF Facility , ESRF, BP220, Grenoble, France.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Bohic
authors.affiliation: CIIL, Inserm U 1019, UMR CNRS 8024, Institut Pasteur de Lille , 1 rue du Pr Calmette, 59019 Lille Cedex, France.
authors.forename: Daniel
authors.initials: D
authors.lastname: Dive
authors.affiliation: Université Lille 1 , UGSF, CNRS UMR 8576, IFR 147, 59650 Villeneuve d'Ascq Cédex, France.
authors.forename: Yann
authors.initials: Y
authors.lastname: Guérardel
authors.affiliation: ESRF Facility , ESRF, BP220, Grenoble, France.
authors.forename: Peter
authors.initials: P
authors.lastname: Cloetens
authors.affiliation: CIIL, Inserm U 1019, UMR CNRS 8024, Institut Pasteur de Lille , 1 rue du Pr Calmette, 59019 Lille Cedex, France.
authors.forename: Jamal
authors.initials: J
authors.lastname: Khalife
authors.affiliation: Université Lille 1 , UGSF, CNRS UMR 8576, IFR 147, 59650 Villeneuve d'Ascq Cédex, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Biot
keywords: antiparasitic agents; chloroquine; drug delivery; drug resistance; ferroquine