Artemether resistance <it>in vitro</it> is linked to mutations in PfATP6 that also interact with mutations in PfMDR1 in travellers returning with <it>Plasmodium falciparum</it> infections
<p>Abstract</p> <p>Background</p> <p>Monitoring resistance phenotypes for <it>Plasmodium falciparum</it>, using <it>in vitro</it> growth assays, and relating findings to parasite genotype has proved particularly challenging for the study of resis...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2012-04-01
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| Series: | Malaria Journal |
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| Online Access: | http://www.malariajournal.com/content/11/1/131 |
| _version_ | 1818484705127825408 |
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| author | Pillai Dylan R Lau Rachel Khairnar Krishna Lepore Rosalba Via Allegra Staines Henry M Krishna Sanjeev |
| author_facet | Pillai Dylan R Lau Rachel Khairnar Krishna Lepore Rosalba Via Allegra Staines Henry M Krishna Sanjeev |
| author_sort | Pillai Dylan R |
| collection | DOAJ |
| description | <p>Abstract</p> <p>Background</p> <p>Monitoring resistance phenotypes for <it>Plasmodium falciparum</it>, using <it>in vitro</it> growth assays, and relating findings to parasite genotype has proved particularly challenging for the study of resistance to artemisinins.</p> <p>Methods</p> <p><it>Plasmodium falciparum</it> 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 <it>pfatp6</it> and <it>pfmdr1</it>.</p> <p>Results</p> <p>Resistance to artemether <it>in vitro</it> was significantly associated with a <it>pfatp6</it> haplotype encoding two amino acid substitutions (<it>pfatp6</it> A623E and S769N; (mean IC<sub>50</sub> (95% CI) values of 8.2 (5.7 – 10.7) for A623/S769 <it>versus</it> 623E/769 N 13.5 (9.8 – 17.3) nM with a mean increase of 65%; p = 0.012). Increased copy number of <it>pfmdr1</it> was not itself associated with increased IC<sub>50</sub> values for artemether, but when interactions between the <it>pfatp6</it> haplotype and increased copy number of <it>pfmdr1</it> were examined together, a highly significant association was noted with IC<sub>50</sub> values for artemether (mean IC<sub>50</sub> (95% CI) values of 8.7 (5.9 – 11.6) <it>versus</it> 16.3 (10.7 – 21.8) nM with a mean increase of 87%; p = 0.0068). Previously described SNPs in <it>pfmdr1</it> are also associated with differences in sensitivity to some artemisinins.</p> <p>Conclusions</p> <p>These findings were further explored in molecular modelling experiments that suggest mutations in <it>pfatp6</it> are unlikely to affect differential binding of artemisinins at their proposed site, whereas there may be differences in such binding associated with mutations in <it>pfmdr1</it>. 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.</p> |
| first_indexed | 2024-12-10T15:58:24Z |
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| institution | Directory Open Access Journal |
| issn | 1475-2875 |
| language | English |
| last_indexed | 2024-12-10T15:58:24Z |
| publishDate | 2012-04-01 |
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| spelling | doaj.art-a7eeb1480e5840e0966e0e4e5c3107f82022-12-22T01:42:34ZengBMCMalaria Journal1475-28752012-04-0111113110.1186/1475-2875-11-131Artemether resistance <it>in vitro</it> is linked to mutations in PfATP6 that also interact with mutations in PfMDR1 in travellers returning with <it>Plasmodium falciparum</it> infectionsPillai Dylan RLau RachelKhairnar KrishnaLepore RosalbaVia AllegraStaines Henry MKrishna Sanjeev<p>Abstract</p> <p>Background</p> <p>Monitoring resistance phenotypes for <it>Plasmodium falciparum</it>, using <it>in vitro</it> growth assays, and relating findings to parasite genotype has proved particularly challenging for the study of resistance to artemisinins.</p> <p>Methods</p> <p><it>Plasmodium falciparum</it> 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 <it>pfatp6</it> and <it>pfmdr1</it>.</p> <p>Results</p> <p>Resistance to artemether <it>in vitro</it> was significantly associated with a <it>pfatp6</it> haplotype encoding two amino acid substitutions (<it>pfatp6</it> A623E and S769N; (mean IC<sub>50</sub> (95% CI) values of 8.2 (5.7 – 10.7) for A623/S769 <it>versus</it> 623E/769 N 13.5 (9.8 – 17.3) nM with a mean increase of 65%; p = 0.012). Increased copy number of <it>pfmdr1</it> was not itself associated with increased IC<sub>50</sub> values for artemether, but when interactions between the <it>pfatp6</it> haplotype and increased copy number of <it>pfmdr1</it> were examined together, a highly significant association was noted with IC<sub>50</sub> values for artemether (mean IC<sub>50</sub> (95% CI) values of 8.7 (5.9 – 11.6) <it>versus</it> 16.3 (10.7 – 21.8) nM with a mean increase of 87%; p = 0.0068). Previously described SNPs in <it>pfmdr1</it> are also associated with differences in sensitivity to some artemisinins.</p> <p>Conclusions</p> <p>These findings were further explored in molecular modelling experiments that suggest mutations in <it>pfatp6</it> are unlikely to affect differential binding of artemisinins at their proposed site, whereas there may be differences in such binding associated with mutations in <it>pfmdr1</it>. 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.</p>http://www.malariajournal.com/content/11/1/131Artemisinin resistance<it>pfmdr1</it><it>pfatp6</it>Gene copy numberMalariaTravellers<it>Plasmodium</it> |
| spellingShingle | Pillai Dylan R Lau Rachel Khairnar Krishna Lepore Rosalba Via Allegra Staines Henry M Krishna Sanjeev Artemether resistance <it>in vitro</it> is linked to mutations in PfATP6 that also interact with mutations in PfMDR1 in travellers returning with <it>Plasmodium falciparum</it> infections Malaria Journal Artemisinin resistance <it>pfmdr1</it> <it>pfatp6</it> Gene copy number Malaria Travellers <it>Plasmodium</it> |
| title | Artemether resistance <it>in vitro</it> is linked to mutations in PfATP6 that also interact with mutations in PfMDR1 in travellers returning with <it>Plasmodium falciparum</it> infections |
| title_full | Artemether resistance <it>in vitro</it> is linked to mutations in PfATP6 that also interact with mutations in PfMDR1 in travellers returning with <it>Plasmodium falciparum</it> infections |
| title_fullStr | Artemether resistance <it>in vitro</it> is linked to mutations in PfATP6 that also interact with mutations in PfMDR1 in travellers returning with <it>Plasmodium falciparum</it> infections |
| title_full_unstemmed | Artemether resistance <it>in vitro</it> is linked to mutations in PfATP6 that also interact with mutations in PfMDR1 in travellers returning with <it>Plasmodium falciparum</it> infections |
| title_short | Artemether resistance <it>in vitro</it> is linked to mutations in PfATP6 that also interact with mutations in PfMDR1 in travellers returning with <it>Plasmodium falciparum</it> infections |
| title_sort | artemether resistance it in vitro it is linked to mutations in pfatp6 that also interact with mutations in pfmdr1 in travellers returning with it plasmodium falciparum it infections |
| topic | Artemisinin resistance <it>pfmdr1</it> <it>pfatp6</it> Gene copy number Malaria Travellers <it>Plasmodium</it> |
| url | http://www.malariajournal.com/content/11/1/131 |
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