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JAC Advance Access originally published online on April 4, 2006
Journal of Antimicrobial Chemotherapy 2006 57(6):1093-1099; doi:10.1093/jac/dkl117
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© The Author 2006. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

In vitro activity of iron-binding compounds against Senegalese isolates of Plasmodium falciparum

B. Pradines1,2,*, A. Tall3, F. Ramiandrasoa4, A. Spiegel3,5, C. Sokhna6, T. Fusai1,2, J. Mosnier1,2, W. Daries1,2, J. F. Trape6, G. Kunesch4, D. Parzy2,7 and C. Rogier1,2

1 Unité de Recherche en Biologie et Epidémiologie Parasitaires, Institut de Médecine Tropicale du Service de Santé des Armées Le Pharo, 13998 Marseille, France 2 Institut Fédératif de la Recherche no 48 13385 Marseille, France 3 Service d'Epidémiologie, Institut Pasteur Dakar, Sénégal 4 Laboratoire de Chimie Bioorganique et Bioinorganique, CNRS URA 1384, Institut de Chimie Moléculaire d'Orsay 91405 Orsay, France 5 Département d'Epidémiologie et de Santé Publique, Ecole d'Application du Service de Santé des Armées 94998 Saint Mandé, France 6 UR 077 de Paludologie Afrotropicale, Institut pour la Recherche et le Développement Dakar, Sénégal 7 Unité de Recherche en Physiopathologie et de Pharmacogénétique Parasitaires, Institut de Médecine Tropicale du Service de Santé des Armées Le Pharo, 13998 Marseille, France

Received 27 September 2005; returned 16 November 2005; revised 9 January 2006; accepted 12 March 2006

*Correspondence address. Unité de Recherche en Biologie et Epidémiologie Parasitaires, Institut de Médecine Tropicale du Service de Santé des Armées, Boulevard Charles Livon, Le Pharo, BP 46, 13998 Marseille, France. Tel: +33-491-150-110; Fax: +33-491-150-164; E-mail: bruno.pradines{at}free.fr

Objectives: The in vitro activities of FR160, a synthetic catecholate siderophore, and two iron-binding agents, desferrioxamine and doxycycline, were evaluated against Plasmodium falciparum isolates. Correlations between these compounds and standard antimalarial drugs (chloroquine, quinine, amodiaquine, pyronaridine, artemether, artesunate, atovaquone, cycloguanil and pyrimethamine) were assessed to determine any degree of cross-resistance.

Methods: Between October 1997 and February 1998, and September and November 1998, 189 P. falciparum isolates were obtained in Dielmo and Ndiop (Dakar). Their susceptibilities were assessed using an isotopic, microwell format, drug susceptibility test.

Results: The 137 inhibitory concentrations (IC50) values of FR160 ranged from 0.1 to 10 µM and the geometric mean IC50 was 1.48 µM (95% CI = 1.29–1.68 µM). The geometric mean IC50 of doxycycline for 121 isolates was 18.9 µM (95% CI = 16.8–21.3 µM) and that of desferrioxamine for 73 isolates was 20.7 µM (95% CI = 17.3–24.8 µM). FR160 was significantly less active against the chloroquine-resistant isolates (P < 0.0001). The mean IC50s of doxycycline were significantly higher for the chloroquine-susceptible isolates than for the resistant parasites (P = 0.0447). There was a weak correlation between the responses to FR160, desferrioxamine or doxycycline and those to the other antimalarial compounds (r2 < 0.22).

Conclusions: The activities of FR160 and desferrioxamine, determined for P. falciparum clones, were confirmed against 137 isolates. The coefficients of determination between the responses to FR160, doxycycline or desferrioxamine and those to all the antimalarial drugs tested are too weak to suggest cross-resistance. FR160 could be a rationale partner to use in combination with doxycycline.

Keywords: malaria , iron chelation , chemotherapy , antimalarial drugs , Senegal


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