Cargando…
UDP-galactose and Acetyl-CoA transporters as Plasmodium multidrug resistance genes
A molecular understanding of drug resistance mechanisms enables surveillance of the effectiveness of new antimicrobial therapies during development and deployment in the field. We used conventional drug resistance selection as well as a regime of limiting dilution at early stages of drug treatment t...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
2016
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5575994/ https://www.ncbi.nlm.nih.gov/pubmed/27642791 http://dx.doi.org/10.1038/nmicrobiol.2016.166 |
_version_ | 1783260131341893632 |
---|---|
author | Lim, Michelle Yi-Xiu LaMonte, Gregory Lee, Marcus C.S. Reimer, Christin Tan, Bee Huat Corey, Victoria Tjahjadi, Bianca F. Chua, Adeline Nachon, Marie Wintjens, René Gedeck, Peter Malleret, Benoit Renia, Laurent Bonamy, Ghislain M.C. Ho, Paul Chi-Lui Yeung, Bryan K. S. Chow, Eric D. Lim, Liting Fidock, David A. Diagana, Thierry T. Winzeler, Elizabeth A. Bifani, Pablo |
author_facet | Lim, Michelle Yi-Xiu LaMonte, Gregory Lee, Marcus C.S. Reimer, Christin Tan, Bee Huat Corey, Victoria Tjahjadi, Bianca F. Chua, Adeline Nachon, Marie Wintjens, René Gedeck, Peter Malleret, Benoit Renia, Laurent Bonamy, Ghislain M.C. Ho, Paul Chi-Lui Yeung, Bryan K. S. Chow, Eric D. Lim, Liting Fidock, David A. Diagana, Thierry T. Winzeler, Elizabeth A. Bifani, Pablo |
author_sort | Lim, Michelle Yi-Xiu |
collection | PubMed |
description | A molecular understanding of drug resistance mechanisms enables surveillance of the effectiveness of new antimicrobial therapies during development and deployment in the field. We used conventional drug resistance selection as well as a regime of limiting dilution at early stages of drug treatment to probe two antimalarial imidazolopiperazines, KAF156 and GNF179. The latter approach permits isolation of low-fitness mutants that might otherwise be out-competed during selection. Whole-genome sequencing of 24 independently-derived resistant P. falciparum clones revealed four parasites with mutations in the known cyclic amine resistance locus (pfcarl), and a further 20 with mutations in two previously unreported P. falciparum drug resistance genes, an acetyl-CoA transporter (pfact) and a UDP-galactose transporter (pfugt). Mutations were validated both in vitro by CRISPR editing in P. falciparum, and in vivo by evolution of resistant P. berghei mutants. Both PfACT and PfUGT were localized to the endoplasmic reticulum by fluorescence microscopy. As mutations in pfact and pfugt conveyed resistance against additional unrelated chemical scaffolds, these genes are likely to be involved in broad mechanisms of antimalarial drug resistance. |
format | Online Article Text |
id | pubmed-5575994 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
record_format | MEDLINE/PubMed |
spelling | pubmed-55759942017-08-30 UDP-galactose and Acetyl-CoA transporters as Plasmodium multidrug resistance genes Lim, Michelle Yi-Xiu LaMonte, Gregory Lee, Marcus C.S. Reimer, Christin Tan, Bee Huat Corey, Victoria Tjahjadi, Bianca F. Chua, Adeline Nachon, Marie Wintjens, René Gedeck, Peter Malleret, Benoit Renia, Laurent Bonamy, Ghislain M.C. Ho, Paul Chi-Lui Yeung, Bryan K. S. Chow, Eric D. Lim, Liting Fidock, David A. Diagana, Thierry T. Winzeler, Elizabeth A. Bifani, Pablo Nat Microbiol Article A molecular understanding of drug resistance mechanisms enables surveillance of the effectiveness of new antimicrobial therapies during development and deployment in the field. We used conventional drug resistance selection as well as a regime of limiting dilution at early stages of drug treatment to probe two antimalarial imidazolopiperazines, KAF156 and GNF179. The latter approach permits isolation of low-fitness mutants that might otherwise be out-competed during selection. Whole-genome sequencing of 24 independently-derived resistant P. falciparum clones revealed four parasites with mutations in the known cyclic amine resistance locus (pfcarl), and a further 20 with mutations in two previously unreported P. falciparum drug resistance genes, an acetyl-CoA transporter (pfact) and a UDP-galactose transporter (pfugt). Mutations were validated both in vitro by CRISPR editing in P. falciparum, and in vivo by evolution of resistant P. berghei mutants. Both PfACT and PfUGT were localized to the endoplasmic reticulum by fluorescence microscopy. As mutations in pfact and pfugt conveyed resistance against additional unrelated chemical scaffolds, these genes are likely to be involved in broad mechanisms of antimalarial drug resistance. 2016-09-19 /pmc/articles/PMC5575994/ /pubmed/27642791 http://dx.doi.org/10.1038/nmicrobiol.2016.166 Text en Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms Reprints and permission information are 742 available online at www.nature.com/reprints (http://www.nature.com/reprints) . |
spellingShingle | Article Lim, Michelle Yi-Xiu LaMonte, Gregory Lee, Marcus C.S. Reimer, Christin Tan, Bee Huat Corey, Victoria Tjahjadi, Bianca F. Chua, Adeline Nachon, Marie Wintjens, René Gedeck, Peter Malleret, Benoit Renia, Laurent Bonamy, Ghislain M.C. Ho, Paul Chi-Lui Yeung, Bryan K. S. Chow, Eric D. Lim, Liting Fidock, David A. Diagana, Thierry T. Winzeler, Elizabeth A. Bifani, Pablo UDP-galactose and Acetyl-CoA transporters as Plasmodium multidrug resistance genes |
title | UDP-galactose and Acetyl-CoA transporters as Plasmodium multidrug resistance genes |
title_full | UDP-galactose and Acetyl-CoA transporters as Plasmodium multidrug resistance genes |
title_fullStr | UDP-galactose and Acetyl-CoA transporters as Plasmodium multidrug resistance genes |
title_full_unstemmed | UDP-galactose and Acetyl-CoA transporters as Plasmodium multidrug resistance genes |
title_short | UDP-galactose and Acetyl-CoA transporters as Plasmodium multidrug resistance genes |
title_sort | udp-galactose and acetyl-coa transporters as plasmodium multidrug resistance genes |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5575994/ https://www.ncbi.nlm.nih.gov/pubmed/27642791 http://dx.doi.org/10.1038/nmicrobiol.2016.166 |
work_keys_str_mv | AT limmichelleyixiu udpgalactoseandacetylcoatransportersasplasmodiummultidrugresistancegenes AT lamontegregory udpgalactoseandacetylcoatransportersasplasmodiummultidrugresistancegenes AT leemarcuscs udpgalactoseandacetylcoatransportersasplasmodiummultidrugresistancegenes AT reimerchristin udpgalactoseandacetylcoatransportersasplasmodiummultidrugresistancegenes AT tanbeehuat udpgalactoseandacetylcoatransportersasplasmodiummultidrugresistancegenes AT coreyvictoria udpgalactoseandacetylcoatransportersasplasmodiummultidrugresistancegenes AT tjahjadibiancaf udpgalactoseandacetylcoatransportersasplasmodiummultidrugresistancegenes AT chuaadeline udpgalactoseandacetylcoatransportersasplasmodiummultidrugresistancegenes AT nachonmarie udpgalactoseandacetylcoatransportersasplasmodiummultidrugresistancegenes AT wintjensrene udpgalactoseandacetylcoatransportersasplasmodiummultidrugresistancegenes AT gedeckpeter udpgalactoseandacetylcoatransportersasplasmodiummultidrugresistancegenes AT malleretbenoit udpgalactoseandacetylcoatransportersasplasmodiummultidrugresistancegenes AT renialaurent udpgalactoseandacetylcoatransportersasplasmodiummultidrugresistancegenes AT bonamyghislainmc udpgalactoseandacetylcoatransportersasplasmodiummultidrugresistancegenes AT hopaulchilui udpgalactoseandacetylcoatransportersasplasmodiummultidrugresistancegenes AT yeungbryanks udpgalactoseandacetylcoatransportersasplasmodiummultidrugresistancegenes AT chowericd udpgalactoseandacetylcoatransportersasplasmodiummultidrugresistancegenes AT limliting udpgalactoseandacetylcoatransportersasplasmodiummultidrugresistancegenes AT fidockdavida udpgalactoseandacetylcoatransportersasplasmodiummultidrugresistancegenes AT diaganathierryt udpgalactoseandacetylcoatransportersasplasmodiummultidrugresistancegenes AT winzelerelizabetha udpgalactoseandacetylcoatransportersasplasmodiummultidrugresistancegenes AT bifanipablo udpgalactoseandacetylcoatransportersasplasmodiummultidrugresistancegenes |