Deciphering the resistance-counteracting functions of the antimalarial ferroquine in Plasmodium falciparum-infected erythrocytes

Abstract : he aminoquinoline chloroquine (CO) 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.
Type de document :
Article dans une revue
ACS Medicinal Chemistry Letters, American Chemical Society, 2012, 3 (6), pp.480-483
Liste complète des métadonnées

Littérature citée [26 références]  Voir  Masquer  Télécharger

http://www.hal.inserm.fr/inserm-00739069
Contributeur : Raphael Serduc <>
Soumis le : vendredi 5 octobre 2012 - 16:01:20
Dernière modification le : mardi 3 juillet 2018 - 11:38:13
Document(s) archivé(s) le : vendredi 16 décembre 2016 - 21:33:42

Fichier

 Accès restreint
Fichier visible le : jamais

Connectez-vous pour demander l'accès au fichier

Identifiants

  • HAL Id : inserm-00739069, version 1

Collections

Citation

Faustine Dubar, Sylvain Bohic, Daniel Dive, Yann Guérardel, Peter Cloetens, et al.. Deciphering the resistance-counteracting functions of the antimalarial ferroquine in Plasmodium falciparum-infected erythrocytes. ACS Medicinal Chemistry Letters, American Chemical Society, 2012, 3 (6), pp.480-483. 〈inserm-00739069〉

Partager

Métriques

Consultations de la notice

439