Artemether resistance in vitro is linked to mutations in PfATP6 that also interact with mutations in PfMDR1 in travellers returning with Plasmodium falciparum infections

Malaria Journal

Research

Henry M Staines¹  Sanjeev Krishna¹  Dylan R Pillai²  Rosalba Lepore³  Allegra Via³  Rachel Lau⁴  Krishna Khairnar⁴ 

[1] Centre for Infection and Immunity, Division of Clinical Sciences, St. George’s, University of London, SW17 0RE, London, UK;Department of Pathology and Laboratory Medicine, Medicine, and Microbiology & Infectious Diseases, University of Calgary, Alberta, Canada;Department of Physics, Sapienza University of Rome, Rome, Italy;Public Health Laboratory, Toronto, Ontario, Canada;

关键词: Artemisinin resistance;    pfmdr1;    pfatp6;    Gene copy number;    Malaria;    Travellers;    Plasmodium;   

DOI  :  10.1186/1475-2875-11-131

 received in 2012-02-01, accepted in 2012-04-27,  发布年份 2012

来源: Springer

【 摘 要 】

BackgroundMonitoring resistance phenotypes for Plasmodium falciparum, using in vitro growth assays, and relating findings to parasite genotype has proved particularly challenging for the study of resistance to artemisinins.MethodsPlasmodium falciparum isolates cultured from 28 returning travellers diagnosed with malaria were assessed for sensitivity to artemisinin, artemether, dihydroartemisinin and artesunate and findings related to mutations in pfatp6 and pfmdr1.ResultsResistance to artemether in vitro was significantly associated with a pfatp6 haplotype encoding two amino acid substitutions (pfatp6 A623E and S769N; (mean IC50 (95% CI) values of 8.2 (5.7 – 10.7) for A623/S769 versus 623E/769 N 13.5 (9.8 – 17.3) nM with a mean increase of 65%; p = 0.012). Increased copy number of pfmdr1 was not itself associated with increased IC50 values for artemether, but when interactions between the pfatp6 haplotype and increased copy number of pfmdr1 were examined together, a highly significant association was noted with IC50 values for artemether (mean IC50 (95% CI) values of 8.7 (5.9 – 11.6) versus 16.3 (10.7 – 21.8) nM with a mean increase of 87%; p = 0.0068). Previously described SNPs in pfmdr1 are also associated with differences in sensitivity to some artemisinins.ConclusionsThese findings were further explored in molecular modelling experiments that suggest mutations in pfatp6 are unlikely to affect differential binding of artemisinins at their proposed site, whereas there may be differences in such binding associated with mutations in pfmdr1. Implications for a hypothesis that artemisinin resistance may be exacerbated by interactions between PfATP6 and PfMDR1 and for epidemiological studies to monitor emerging resistance are discussed.

【 授权许可】

Unknown   
© Pillai et al.; licensee BioMed Central Ltd. 2012. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.