Absence of association between pyronaridine in vitro responses and polymorphisms in genes involved in quinoline resistance in Plasmodium falciparum

A Yeka; AB Sidhu; AB Sidhu; AM Dondorp; B Pradines; B Pradines; B Pradines; B Pradines; BR Shao; Bruno Pradines; C Lambros; Christophe Rogier; Claude Oeuvray; DA Fidock; EA Ashley; EI Elueze; Eric Baret; Eric Didillon; F Kurth; F Nawaz; F Nosten; GE Childs; H Bogreau; H Noedl; J Le Bras; J Qi; J Qi; J Ursing; L Vivas; L Von Seidlein; LK Basco; M Henry; M Henry; M Henry; M Henry; M Ramharter; Maud Henry; MB Reed; MT Ferdig; NJ White; P Brasseur; P Ringwald; P Ringwald; Q Bassat; RN Price; RT Eastman; Rémy Amalvict; S Looareesuwan; Sébastien Briolant; TM Davis; V Durrand; VI Carrara; WO Rogers; Z Premji

Absence of association between pyronaridine in vitro responses and polymorphisms in genes involved in quinoline resistance in Plasmodium falciparum

Abstract

Abstract Background The aim of the present work was to assess the <it>in vitro </it>cross-resistance of pyronaridine with other quinoline drugs, artesunate and several other commonly used anti-malarials and to evaluate whether decreased susceptibility to pyronaridine could be associated with genetic polymorphisms in genes involved in reduced quinoline susceptibility, such as <it>pfcrt</it>, <it>pfmdr1</it>, <it>pfmrp </it>and <it>pfnhe</it>. Methods The <it>in vitro </it>chemosusceptibility profiles of 23 strains of <it>Plasmodium falciparum </it>were analysed by the standard 42-hour 3H-hypoxanthine uptake inhibition method for pyronaridine, artesunate, chloroquine, monodesethylamodiaquine, quinine, mefloquine, lumefantrine, atovaquone, pyrimethamine and doxycycline. Genotypes were assessed for <it>pfcrt</it>, <it>pfmdr1</it>, <it>pfnhe-1 </it>and <it>pfmrp </it>genes. Results The IC50 values for pyronaridine ranged from 15 to 49 nM (geometric mean = 23.1 nM). A significant positive correlation was found between responses to pyronaridine and responses to artesunate (<it>r2 </it>= 0.20; <it>P </it>= 0.0317) but too low to suggest cross-resistance. No significant correlation was found between pyronaridine IC50 and responses to other anti-malarials. Significant associations were not found between pyronaridine IC50 and polymorphisms in <it>pfcrt</it>, <it>pfmdr1</it>, <it>pfmrp </it>or <it>pfnhe-1</it>. Conclusion There was an absence of cross-resistance between pyronaridine and quinolines, and the IC50 values for pyronaridine were found to be unrelated to mutations in the transport protein genes <it>pfcrt</it>, <it>pfmdr1</it>, <it>pfmrp </it>or <it>pfnhe-1</it>, known to be involved in quinoline resistance. These results confirm the interest and the efficacy of the use of a combination of pyronaridine and artesunate in areas in which parasites are resistant to quinolines.</p