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Antimicrobial Agents and Chemotherapy, August 2008, p. 2755-2759, Vol. 52, No. 8
0066-4804/08/$08.00+0     doi:10.1128/AAC.00060-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

In Vitro Activity of Ferroquine Is Independent of Polymorphisms in Transport Protein Genes Implicated in Quinoline Resistance in Plasmodium falciparum{triangledown}

Maud Henry,1,2 Sébastien Briolant,1,2 Albin Fontaine,1,2 Joel Mosnier,1,2 Eric Baret,1,2 Rémy Amalvict,1,2 Thierry Fusaï,1,2 Laurent Fraisse,3 Christophe Rogier,1,2 and Bruno Pradines1,2*

Unité de Recherche en Biologie et Epidémiologie Parasitaires, Institut de Médecine Tropicale du Service de Santé des Armées, Marseille, France,1 Unité de Recherche pour les Maladies Infectieuses et Tropicales Emergentes, Unité Mixte de Recherche 6236, Marseille, France,2 Sanofi-Aventis Recherche et Développement, Sanofi-Aventis, Toulouse, France3

Received 15 January 2008/ Returned for modification 17 April 2008/ Accepted 19 May 2008

The in vitro activity of ferroquine (FQ) (SR97193), a 4-aminoquinoline antimalarial compound that contains a ferrocenic nucleus, against 15 Plasmodium falciparum strains was assessed and compared with those of chloroquine (CQ), quinine (QN), monodesethylamodiaquine (MDAQ), and mefloquine (MQ). These 15 strains were genotyped for polymorphisms in quinoline resistance-associated genes such as Pfcrt, Pfmdr1, Pfmrp, and Pfnhe-1. FQ was highly active against CQ-resistant parasites or in parasites with reduced susceptibility to QN, MDAQ, or MQ. Encouragingly, we did not find a correlation between responses to FQ and those to other quinoline drugs. These results suggest that no cross-resistance exits between FQ and CQ or quinoline antimalarial drugs. Mutations in codons 74, 75, 76, 220, 271, 326, 356, and 371 of the Pfcrt gene; codons 86, 184, 1034, 1042, and 1246 of the Pfmdr1 gene; and codons 191 and 437 of the Pfmrp gene were not significantly associated with P. falciparum susceptibility to FQ. Neither the number of ms4760 DNNND or DDNHNDNHNN repeats in Pfnhe-1 nor the profile of ms4760 was significantly associated with the FQ in vitro response. These data suggest the FQ may not interact with transport proteins in quinoline-resistant parasites. The present results justify further clinical trials of FQ in multidrug resistance areas.

* Corresponding author. Mailing address: Unité de Recherche en Biologie et Épidémiologie Parasitaires, Institut de Médecine Tropicale du Service de Santé des Armées, Boulevard Charles Livon, Parc le Pharo, 13998 Marseille Armées, France. Phone: 33 4 91 15 01 10. Fax: 33 4 91 15 01 64. E-mail: bruno.pradines{at}free.fr

{triangledown} Published ahead of print on 27 May 2008.

Antimicrobial Agents and Chemotherapy, August 2008, p. 2755-2759, Vol. 52, No. 8
0066-4804/08/$08.00+0     doi:10.1128/AAC.00060-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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