Publicação
Globally prevalent PfMDR1 mutations modulate Plasmodium falciparum susceptibility to artemisinin-based combination therapies
| Resumo: | Antimalarial chemotherapy, globally reliant on artemisinin-based combination therapies (ACTs), is threatened by the spread of drug resistance in Plasmodium falciparum parasites. Here we use zinc-finger nucleases to genetically modify the multidrug resistance-1 transporter PfMDR1 at amino acids 86 and 184, and demonstrate that the widely prevalent N86Y mutation augments resistance to the ACT partner drug amodiaquine and the former first-line agent chloroquine. In contrast, N86Y increases parasite susceptibility to the partner drugs lumefantrine and mefloquine, and the active artemisinin metabolite dihydroartemisinin. The PfMDR1 N86 plus Y184F isoform moderately reduces piperaquine potency in strains expressing an Asian/African variant of the chloroquine resistance transporter PfCRT. Mutations in both digestive vacuole-resident transporters are thought to differentially regulate ACT drug interactions with host haem, a product of parasite-mediated haemoglobin degradation. Global mapping of these mutations illustrates where the different ACTs could be selectively deployed to optimize treatment based on regional differences in PfMDR1 haplotypes. |
|---|---|
| Autores principais: | Veiga, Maria Isabel Mendes |
| Outros Autores: | Dhingra, Satish K.; Henrich, Philipp P.; Straimer, Judith; Gnädig, Nina; Uhlemann, Anne-Catrin; Martin, Rowena E.; Lehane, Adele M.; Fidock, David A. |
| Assunto: | Ciências Médicas::Medicina Básica |
| Ano: | 2016 |
| País: | Portugal |
| Tipo de documento: | artigo |
| Tipo de acesso: | acesso aberto |
| Instituição associada: | Universidade do Minho |
| Idioma: | inglês |
| Origem: | RepositóriUM - Universidade do Minho |
| _version_ | 1867437871039774720 |
|---|---|
| author | Veiga, Maria Isabel Mendes |
| author2 | Dhingra, Satish K. Henrich, Philipp P. Straimer, Judith Gnädig, Nina Uhlemann, Anne-Catrin Martin, Rowena E. Lehane, Adele M. Fidock, David A. |
| author2_role | author author author author author author author author |
| author_facet | Veiga, Maria Isabel Mendes Dhingra, Satish K. Henrich, Philipp P. Straimer, Judith Gnädig, Nina Uhlemann, Anne-Catrin Martin, Rowena E. Lehane, Adele M. Fidock, David A. |
| author_role | author |
| contributor_name_str_mv | RepositóriUM - Universidade do Minho |
| country_str | PT |
| creators_json_txt | [{\"Person.name\":\"Veiga, Maria Isabel Mendes\"},{\"Person.name\":\"Dhingra, Satish K.\"},{\"Person.name\":\"Henrich, Philipp P.\"},{\"Person.name\":\"Straimer, Judith\"},{\"Person.name\":\"Gnädig, Nina\"},{\"Person.name\":\"Uhlemann, Anne-Catrin\"},{\"Person.name\":\"Martin, Rowena E.\"},{\"Person.name\":\"Lehane, Adele M.\"},{\"Person.name\":\"Fidock, David A.\"}] |
| datacite.contributors.contributor.contributorName.fl_str_mv | RepositóriUM - Universidade do Minho |
| datacite.creators.creator.creatorName.fl_str_mv | Veiga, Maria Isabel Mendes Dhingra, Satish K. Henrich, Philipp P. Straimer, Judith Gnädig, Nina Uhlemann, Anne-Catrin Martin, Rowena E. Lehane, Adele M. Fidock, David A. |
| datacite.date.Accepted.fl_str_mv | 2016-05-01T00:00:00Z |
| datacite.date.available.fl_str_mv | 2017-04-12T16:41:06Z |
| datacite.date.embargoed.fl_str_mv | 2017-04-12T16:41:06Z |
| datacite.rights.fl_str_mv | http://purl.org/coar/access_right/c_abf2 |
| datacite.subjects.subject.fl_str_mv | Ciências Médicas::Medicina Básica |
| datacite.titles.title.fl_str_mv | Globally prevalent PfMDR1 mutations modulate Plasmodium falciparum susceptibility to artemisinin-based combination therapies |
| dc.contributor.none.fl_str_mv | RepositóriUM - Universidade do Minho |
| dc.creator.none.fl_str_mv | Veiga, Maria Isabel Mendes Dhingra, Satish K. Henrich, Philipp P. Straimer, Judith Gnädig, Nina Uhlemann, Anne-Catrin Martin, Rowena E. Lehane, Adele M. Fidock, David A. |
| dc.date.Accepted.fl_str_mv | 2016-05-01T00:00:00Z |
| dc.date.available.fl_str_mv | 2017-04-12T16:41:06Z |
| dc.date.embargoed.fl_str_mv | 2017-04-12T16:41:06Z |
| dc.format.none.fl_str_mv | application/pdf |
| dc.identifier.none.fl_str_mv | https://hdl.handle.net/1822/45325 |
| dc.language.none.fl_str_mv | eng |
| dc.publisher.none.fl_str_mv | Nature Publishing Group |
| dc.rights.none.fl_str_mv | http://purl.org/coar/access_right/c_abf2 |
| dc.subject.none.fl_str_mv | Ciências Médicas::Medicina Básica |
| dc.title.fl_str_mv | Globally prevalent PfMDR1 mutations modulate Plasmodium falciparum susceptibility to artemisinin-based combination therapies |
| dc.type.none.fl_str_mv | http://purl.org/coar/resource_type/c_6501 |
| description | Antimalarial chemotherapy, globally reliant on artemisinin-based combination therapies (ACTs), is threatened by the spread of drug resistance in Plasmodium falciparum parasites. Here we use zinc-finger nucleases to genetically modify the multidrug resistance-1 transporter PfMDR1 at amino acids 86 and 184, and demonstrate that the widely prevalent N86Y mutation augments resistance to the ACT partner drug amodiaquine and the former first-line agent chloroquine. In contrast, N86Y increases parasite susceptibility to the partner drugs lumefantrine and mefloquine, and the active artemisinin metabolite dihydroartemisinin. The PfMDR1 N86 plus Y184F isoform moderately reduces piperaquine potency in strains expressing an Asian/African variant of the chloroquine resistance transporter PfCRT. Mutations in both digestive vacuole-resident transporters are thought to differentially regulate ACT drug interactions with host haem, a product of parasite-mediated haemoglobin degradation. Global mapping of these mutations illustrates where the different ACTs could be selectively deployed to optimize treatment based on regional differences in PfMDR1 haplotypes. |
| dirty | 0 |
| eu_rights_str_mv | openAccess |
| format | article |
| fulltext.url.fl_str_mv | https://repositorium.uminho.pt/bitstreams/3d9bb7fb-6dd0-46f9-b717-7e8d02f95f45/download |
| id | rum_3db92d575669e75b411ae90f2fda4e14 |
| identifier.url.fl_str_mv | https://hdl.handle.net/1822/45325 |
| instacron_str | repositorium |
| institution | Universidade do Minho |
| instname_str | Universidade do Minho |
| language | eng |
| network_acronym_str | rum |
| network_name_str | RepositóriUM - Universidade do Minho |
| oai_identifier_str | oai:repositorium.uminho.pt:1822/45325 |
| organization_str_mv | urn:organizationAcronym:repositorium |
| person_str_mv | Veiga, Maria Isabel Mendes Dhingra, Satish K. Henrich, Philipp P. Straimer, Judith Gnädig, Nina Uhlemann, Anne-Catrin Martin, Rowena E. Lehane, Adele M. Fidock, David A. |
| publishDate | 2016 |
| publisher.none.fl_str_mv | Nature Publishing Group |
| reponame_str | RepositóriUM - Universidade do Minho |
| repository_id_str | urn:repositoryAcronym:rum |
| service_str_mv | urn:repositoryAcronym:rum |
| spelling | engNature Publishing GroupporAntimalarial chemotherapy, globally reliant on artemisinin-based combination therapies (ACTs), is threatened by the spread of drug resistance in Plasmodium falciparum parasites. Here we use zinc-finger nucleases to genetically modify the multidrug resistance-1 transporter PfMDR1 at amino acids 86 and 184, and demonstrate that the widely prevalent N86Y mutation augments resistance to the ACT partner drug amodiaquine and the former first-line agent chloroquine. In contrast, N86Y increases parasite susceptibility to the partner drugs lumefantrine and mefloquine, and the active artemisinin metabolite dihydroartemisinin. The PfMDR1 N86 plus Y184F isoform moderately reduces piperaquine potency in strains expressing an Asian/African variant of the chloroquine resistance transporter PfCRT. Mutations in both digestive vacuole-resident transporters are thought to differentially regulate ACT drug interactions with host haem, a product of parasite-mediated haemoglobin degradation. Global mapping of these mutations illustrates where the different ACTs could be selectively deployed to optimize treatment based on regional differences in PfMDR1 haplotypes.application/pdfporGlobally prevalent PfMDR1 mutations modulate Plasmodium falciparum susceptibility to artemisinin-based combination therapiesVeiga, Maria Isabel MendesDhingra, Satish K.Henrich, Philipp P.Straimer, JudithGnädig, NinaUhlemann, Anne-CatrinMartin, Rowena E.Lehane, Adele M.Fidock, David A.HostingInstitutionOrganizationalRepositóriUM - Universidade do Minhoe-mailmailto:repositorium@usdb.uminho.ptrepositorium@usdb.uminho.ptCITATIONVeiga, M. I., Dhingra, S. K., Henrich, P. P., Straimer, J., Gnädig, N., Uhlemann, A. C., . . . Fidock, D. A. (2016). Globally prevalent PfMDR1 mutations modulate Plasmodium falciparum susceptibility to artemisinin-based combination therapies. Nature Communications, 7. doi: 10.1038/ncomms11553PMID27189525ISSNIsPartOf2041-1723DOIIsPartOf10.1038/ncomms115532017-04-12T16:41:06Z2016-052015-102017-02-13T13:01:01Z2016-05-01T00:00:00ZHandlehttps://hdl.handle.net/1822/45325http://purl.org/coar/access_right/c_abf2open accesshttp://www.oecd.org/science/inno/38235147.pdfFields of Science and Technology (FOS)Ciências Médicas::Medicina Básica1379153 bytesliteraturehttp://purl.org/coar/resource_type/c_6501journal articlehttp://purl.org/coar/access_right/c_abf2application/pdffulltexthttps://repositorium.uminho.pt/bitstreams/3d9bb7fb-6dd0-46f9-b717-7e8d02f95f45/download |
| spellingShingle | Globally prevalent PfMDR1 mutations modulate Plasmodium falciparum susceptibility to artemisinin-based combination therapies Veiga, Maria Isabel Mendes Ciências Médicas::Medicina Básica |
| status | SINGLETON |
| subject.other.fl_str_mv | Ciências Médicas::Medicina Básica |
| title | Globally prevalent PfMDR1 mutations modulate Plasmodium falciparum susceptibility to artemisinin-based combination therapies |
| title_full | Globally prevalent PfMDR1 mutations modulate Plasmodium falciparum susceptibility to artemisinin-based combination therapies |
| title_fullStr | Globally prevalent PfMDR1 mutations modulate Plasmodium falciparum susceptibility to artemisinin-based combination therapies |
| title_full_unstemmed | Globally prevalent PfMDR1 mutations modulate Plasmodium falciparum susceptibility to artemisinin-based combination therapies |
| title_short | Globally prevalent PfMDR1 mutations modulate Plasmodium falciparum susceptibility to artemisinin-based combination therapies |
| title_sort | Globally prevalent PfMDR1 mutations modulate Plasmodium falciparum susceptibility to artemisinin-based combination therapies |
| topic | Ciências Médicas::Medicina Básica |
| topic_facet | Ciências Médicas::Medicina Básica |
| url | https://hdl.handle.net/1822/45325 |
| visible | 1 |