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Mutations in the Plasmodium falciparum Cyclic Amine Resistance Locus (PfCARL) Confer Multidrug Resistance
Mutations in the Plasmodium falciparum cyclic amine resistance locus (PfCARL) are associated with parasite resistance to the imidazolopiperazines, a potent class of novel antimalarial compounds that display both prophylactic and transmission-blocking activity, in addition to activity against blood-s...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society for Microbiology
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4958248/ https://www.ncbi.nlm.nih.gov/pubmed/27381290 http://dx.doi.org/10.1128/mBio.00696-16 |
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author | LaMonte, Gregory Lim, Michelle Yi-Xiu Wree, Melanie Reimer, Christin Nachon, Marie Corey, Victoria Gedeck, Peter Plouffe, David Du, Alan Figueroa, Nelissa Yeung, Bryan Bifani, Pablo Winzeler, Elizabeth A. |
author_facet | LaMonte, Gregory Lim, Michelle Yi-Xiu Wree, Melanie Reimer, Christin Nachon, Marie Corey, Victoria Gedeck, Peter Plouffe, David Du, Alan Figueroa, Nelissa Yeung, Bryan Bifani, Pablo Winzeler, Elizabeth A. |
author_sort | LaMonte, Gregory |
collection | PubMed |
description | Mutations in the Plasmodium falciparum cyclic amine resistance locus (PfCARL) are associated with parasite resistance to the imidazolopiperazines, a potent class of novel antimalarial compounds that display both prophylactic and transmission-blocking activity, in addition to activity against blood-stage parasites. Here, we show that pfcarl encodes a protein, with a predicted molecular weight of 153 kDa, that localizes to the cis-Golgi apparatus of the parasite in both asexual and sexual blood stages. Utilizing clustered regularly interspaced short palindromic repeat (CRISPR)-mediated gene introduction of 5 variants (L830V, S1076N/I, V1103L, and I1139K), we demonstrate that mutations in pfcarl are sufficient to generate resistance against the imidazolopiperazines in both asexual and sexual blood-stage parasites. We further determined that the mutant PfCARL protein confers resistance to several structurally unrelated compounds. These data suggest that PfCARL modulates the levels of small-molecule inhibitors that affect Golgi-related processes, such as protein sorting or membrane trafficking, and is therefore an important mechanism of resistance in malaria parasites. |
format | Online Article Text |
id | pubmed-4958248 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | American Society for Microbiology |
record_format | MEDLINE/PubMed |
spelling | pubmed-49582482016-07-25 Mutations in the Plasmodium falciparum Cyclic Amine Resistance Locus (PfCARL) Confer Multidrug Resistance LaMonte, Gregory Lim, Michelle Yi-Xiu Wree, Melanie Reimer, Christin Nachon, Marie Corey, Victoria Gedeck, Peter Plouffe, David Du, Alan Figueroa, Nelissa Yeung, Bryan Bifani, Pablo Winzeler, Elizabeth A. mBio Research Article Mutations in the Plasmodium falciparum cyclic amine resistance locus (PfCARL) are associated with parasite resistance to the imidazolopiperazines, a potent class of novel antimalarial compounds that display both prophylactic and transmission-blocking activity, in addition to activity against blood-stage parasites. Here, we show that pfcarl encodes a protein, with a predicted molecular weight of 153 kDa, that localizes to the cis-Golgi apparatus of the parasite in both asexual and sexual blood stages. Utilizing clustered regularly interspaced short palindromic repeat (CRISPR)-mediated gene introduction of 5 variants (L830V, S1076N/I, V1103L, and I1139K), we demonstrate that mutations in pfcarl are sufficient to generate resistance against the imidazolopiperazines in both asexual and sexual blood-stage parasites. We further determined that the mutant PfCARL protein confers resistance to several structurally unrelated compounds. These data suggest that PfCARL modulates the levels of small-molecule inhibitors that affect Golgi-related processes, such as protein sorting or membrane trafficking, and is therefore an important mechanism of resistance in malaria parasites. American Society for Microbiology 2016-07-05 /pmc/articles/PMC4958248/ /pubmed/27381290 http://dx.doi.org/10.1128/mBio.00696-16 Text en Copyright © 2016 LaMonte et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license (http://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Research Article LaMonte, Gregory Lim, Michelle Yi-Xiu Wree, Melanie Reimer, Christin Nachon, Marie Corey, Victoria Gedeck, Peter Plouffe, David Du, Alan Figueroa, Nelissa Yeung, Bryan Bifani, Pablo Winzeler, Elizabeth A. Mutations in the Plasmodium falciparum Cyclic Amine Resistance Locus (PfCARL) Confer Multidrug Resistance |
title | Mutations in the Plasmodium falciparum Cyclic Amine Resistance Locus (PfCARL) Confer Multidrug Resistance |
title_full | Mutations in the Plasmodium falciparum Cyclic Amine Resistance Locus (PfCARL) Confer Multidrug Resistance |
title_fullStr | Mutations in the Plasmodium falciparum Cyclic Amine Resistance Locus (PfCARL) Confer Multidrug Resistance |
title_full_unstemmed | Mutations in the Plasmodium falciparum Cyclic Amine Resistance Locus (PfCARL) Confer Multidrug Resistance |
title_short | Mutations in the Plasmodium falciparum Cyclic Amine Resistance Locus (PfCARL) Confer Multidrug Resistance |
title_sort | mutations in the plasmodium falciparum cyclic amine resistance locus (pfcarl) confer multidrug resistance |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4958248/ https://www.ncbi.nlm.nih.gov/pubmed/27381290 http://dx.doi.org/10.1128/mBio.00696-16 |
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