Complex polymorphisms in the plasmodium falciparum multidrug resistance protein 2 gene and its contribution to antimalarial response

Plasmodium falciparum has the capacity to escape the actions of essentially all antimalarial drugs. ATP-binding cassette (ABC) transporter proteins are known to cause multidrug resistance in a large range of organisms, including the Apicomplexa parasites. P. falciparum genome analysis has revealed t...

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Main Authors: Veiga, Maria Isabel, Osório, Nuno S., Ferreira, Pedro Eduardo, Franzén, Oscar, Dahlstrom, Sabina, Lum, J. Koji, Nosten, Francois, Gil, José Pedro
Other Authors: School of Biological Sciences
Format: Article
Language:English
Published: 2015
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Online Access:https://hdl.handle.net/10356/100186
http://hdl.handle.net/10220/25681
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Institution: Nanyang Technological University
Language: English
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spelling sg-ntu-dr.10356-1001862023-02-28T17:03:29Z Complex polymorphisms in the plasmodium falciparum multidrug resistance protein 2 gene and its contribution to antimalarial response Veiga, Maria Isabel Osório, Nuno S. Ferreira, Pedro Eduardo Franzén, Oscar Dahlstrom, Sabina Lum, J. Koji Nosten, Francois Gil, José Pedro School of Biological Sciences DRNTU::Science::Biological sciences::Microbiology Plasmodium falciparum has the capacity to escape the actions of essentially all antimalarial drugs. ATP-binding cassette (ABC) transporter proteins are known to cause multidrug resistance in a large range of organisms, including the Apicomplexa parasites. P. falciparum genome analysis has revealed two genes coding for the multidrug resistance protein (MRP) type of ABC transporters: Pfmrp1, previously associated with decreased parasite drug susceptibility, and the poorly studied Pfmrp2. The role of Pfmrp2 polymorphisms in modulating sensitivity to antimalarial drugs has not been established. We herein report a comprehensive account of the Pfmrp2 genetic variability in 46 isolates from Thailand. A notably high frequency of 2.8 single nucleotide polymorphisms (SNPs)/kb was identified for this gene, including some novel SNPs. Additionally, we found that Pfmrp2 harbors a significant number of microindels, some previously not reported. We also investigated the potential association of the identified Pfmrp2 polymorphisms with altered in vitro susceptibility to several antimalarials used in artemisinin-based combination therapy and with parasite clearance time. Association analysis suggested Pfmrp2 polymorphisms modulate the parasite's in vitro response to quinoline antimalarials, including chloroquine, piperaquine, and mefloquine, and association with in vivo parasite clearance. In conclusion, our study reveals that the Pfmrp2 gene is the most diverse ABC transporter known in P. falciparum with a potential role in antimalarial drug resistance. Published version 2015-05-26T08:43:39Z 2019-12-06T20:18:03Z 2015-05-26T08:43:39Z 2019-12-06T20:18:03Z 2014 2014 Journal Article Veiga, M. I., Osório, N. S., Ferreira, P. E., Franzén, O., Dahlstrom, S., Lum, J. K., et al. (2014). Complex polymorphisms in the plasmodium falciparum multidrug resistance protein 2 gene and its contribution to antimalarial response. Antimicrobial agents and chemotherapy, 58(12), 7390-7397. https://hdl.handle.net/10356/100186 http://hdl.handle.net/10220/25681 10.1128/AAC.03337-14 25267670 en Antimicrobial agents and chemotherapy © 2014 American Society for Microbiology. This paper was published in Antimicrobial Agents and Chemotherapy and is made available as an electronic reprint (preprint) with permission of American Society for Microbiology. The paper can be found at the following official DOI: [http://dx.doi.org/10.1128/AAC.03337-14]. One print or electronic copy may be made for personal use only. Systematic or multiple reproduction, distribution to multiple locations via electronic or other means, duplication of any material in this paper for a fee or for commercial purposes, or modification of the content of the paper is prohibited and is subject to penalties under law. 8 p. application/pdf
institution Nanyang Technological University
building NTU Library
continent Asia
country Singapore
Singapore
content_provider NTU Library
collection DR-NTU
language English
topic DRNTU::Science::Biological sciences::Microbiology
spellingShingle DRNTU::Science::Biological sciences::Microbiology
Veiga, Maria Isabel
Osório, Nuno S.
Ferreira, Pedro Eduardo
Franzén, Oscar
Dahlstrom, Sabina
Lum, J. Koji
Nosten, Francois
Gil, José Pedro
Complex polymorphisms in the plasmodium falciparum multidrug resistance protein 2 gene and its contribution to antimalarial response
description Plasmodium falciparum has the capacity to escape the actions of essentially all antimalarial drugs. ATP-binding cassette (ABC) transporter proteins are known to cause multidrug resistance in a large range of organisms, including the Apicomplexa parasites. P. falciparum genome analysis has revealed two genes coding for the multidrug resistance protein (MRP) type of ABC transporters: Pfmrp1, previously associated with decreased parasite drug susceptibility, and the poorly studied Pfmrp2. The role of Pfmrp2 polymorphisms in modulating sensitivity to antimalarial drugs has not been established. We herein report a comprehensive account of the Pfmrp2 genetic variability in 46 isolates from Thailand. A notably high frequency of 2.8 single nucleotide polymorphisms (SNPs)/kb was identified for this gene, including some novel SNPs. Additionally, we found that Pfmrp2 harbors a significant number of microindels, some previously not reported. We also investigated the potential association of the identified Pfmrp2 polymorphisms with altered in vitro susceptibility to several antimalarials used in artemisinin-based combination therapy and with parasite clearance time. Association analysis suggested Pfmrp2 polymorphisms modulate the parasite's in vitro response to quinoline antimalarials, including chloroquine, piperaquine, and mefloquine, and association with in vivo parasite clearance. In conclusion, our study reveals that the Pfmrp2 gene is the most diverse ABC transporter known in P. falciparum with a potential role in antimalarial drug resistance.
author2 School of Biological Sciences
author_facet School of Biological Sciences
Veiga, Maria Isabel
Osório, Nuno S.
Ferreira, Pedro Eduardo
Franzén, Oscar
Dahlstrom, Sabina
Lum, J. Koji
Nosten, Francois
Gil, José Pedro
format Article
author Veiga, Maria Isabel
Osório, Nuno S.
Ferreira, Pedro Eduardo
Franzén, Oscar
Dahlstrom, Sabina
Lum, J. Koji
Nosten, Francois
Gil, José Pedro
author_sort Veiga, Maria Isabel
title Complex polymorphisms in the plasmodium falciparum multidrug resistance protein 2 gene and its contribution to antimalarial response
title_short Complex polymorphisms in the plasmodium falciparum multidrug resistance protein 2 gene and its contribution to antimalarial response
title_full Complex polymorphisms in the plasmodium falciparum multidrug resistance protein 2 gene and its contribution to antimalarial response
title_fullStr Complex polymorphisms in the plasmodium falciparum multidrug resistance protein 2 gene and its contribution to antimalarial response
title_full_unstemmed Complex polymorphisms in the plasmodium falciparum multidrug resistance protein 2 gene and its contribution to antimalarial response
title_sort complex polymorphisms in the plasmodium falciparum multidrug resistance protein 2 gene and its contribution to antimalarial response
publishDate 2015
url https://hdl.handle.net/10356/100186
http://hdl.handle.net/10220/25681
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