Cargando…
Comparative chemical genomics reveal that the spiroindolone antimalarial KAE609 (Cipargamin) is a P-type ATPase inhibitor
The spiroindolones, a new class of antimalarial medicines discovered in a cellular screen, are rendered less active by mutations in a parasite P-type ATPase, PfATP4. We show here that S. cerevisiae also acquires mutations in a gene encoding a P-type ATPase (ScPMA1) after exposure to spiroindolones a...
Autores principales: | , , , , , , , , , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2016
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4904242/ https://www.ncbi.nlm.nih.gov/pubmed/27291296 http://dx.doi.org/10.1038/srep27806 |
_version_ | 1782437116383330304 |
---|---|
author | Goldgof, Gregory M. Durrant, Jacob D. Ottilie, Sabine Vigil, Edgar Allen, Kenneth E. Gunawan, Felicia Kostylev, Maxim Henderson, Kiersten A. Yang, Jennifer Schenken, Jake LaMonte, Gregory M. Manary, Micah J. Murao, Ayako Nachon, Marie Murray, Rebecca Prescott, Maximo McNamara, Case W. Slayman, Carolyn W. Amaro, Rommie E. Suzuki, Yo Winzeler, Elizabeth A. |
author_facet | Goldgof, Gregory M. Durrant, Jacob D. Ottilie, Sabine Vigil, Edgar Allen, Kenneth E. Gunawan, Felicia Kostylev, Maxim Henderson, Kiersten A. Yang, Jennifer Schenken, Jake LaMonte, Gregory M. Manary, Micah J. Murao, Ayako Nachon, Marie Murray, Rebecca Prescott, Maximo McNamara, Case W. Slayman, Carolyn W. Amaro, Rommie E. Suzuki, Yo Winzeler, Elizabeth A. |
author_sort | Goldgof, Gregory M. |
collection | PubMed |
description | The spiroindolones, a new class of antimalarial medicines discovered in a cellular screen, are rendered less active by mutations in a parasite P-type ATPase, PfATP4. We show here that S. cerevisiae also acquires mutations in a gene encoding a P-type ATPase (ScPMA1) after exposure to spiroindolones and that these mutations are sufficient for resistance. KAE609 resistance mutations in ScPMA1 do not confer resistance to unrelated antimicrobials, but do confer cross sensitivity to the alkyl-lysophospholipid edelfosine, which is known to displace ScPma1p from the plasma membrane. Using an in vitro cell-free assay, we demonstrate that KAE609 directly inhibits ScPma1p ATPase activity. KAE609 also increases cytoplasmic hydrogen ion concentrations in yeast cells. Computer docking into a ScPma1p homology model identifies a binding mode that supports genetic resistance determinants and in vitro experimental structure-activity relationships in both P. falciparum and S. cerevisiae. This model also suggests a shared binding site with the dihydroisoquinolones antimalarials. Our data support a model in which KAE609 exerts its antimalarial activity by directly interfering with P-type ATPase activity. |
format | Online Article Text |
id | pubmed-4904242 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-49042422016-06-14 Comparative chemical genomics reveal that the spiroindolone antimalarial KAE609 (Cipargamin) is a P-type ATPase inhibitor Goldgof, Gregory M. Durrant, Jacob D. Ottilie, Sabine Vigil, Edgar Allen, Kenneth E. Gunawan, Felicia Kostylev, Maxim Henderson, Kiersten A. Yang, Jennifer Schenken, Jake LaMonte, Gregory M. Manary, Micah J. Murao, Ayako Nachon, Marie Murray, Rebecca Prescott, Maximo McNamara, Case W. Slayman, Carolyn W. Amaro, Rommie E. Suzuki, Yo Winzeler, Elizabeth A. Sci Rep Article The spiroindolones, a new class of antimalarial medicines discovered in a cellular screen, are rendered less active by mutations in a parasite P-type ATPase, PfATP4. We show here that S. cerevisiae also acquires mutations in a gene encoding a P-type ATPase (ScPMA1) after exposure to spiroindolones and that these mutations are sufficient for resistance. KAE609 resistance mutations in ScPMA1 do not confer resistance to unrelated antimicrobials, but do confer cross sensitivity to the alkyl-lysophospholipid edelfosine, which is known to displace ScPma1p from the plasma membrane. Using an in vitro cell-free assay, we demonstrate that KAE609 directly inhibits ScPma1p ATPase activity. KAE609 also increases cytoplasmic hydrogen ion concentrations in yeast cells. Computer docking into a ScPma1p homology model identifies a binding mode that supports genetic resistance determinants and in vitro experimental structure-activity relationships in both P. falciparum and S. cerevisiae. This model also suggests a shared binding site with the dihydroisoquinolones antimalarials. Our data support a model in which KAE609 exerts its antimalarial activity by directly interfering with P-type ATPase activity. Nature Publishing Group 2016-06-13 /pmc/articles/PMC4904242/ /pubmed/27291296 http://dx.doi.org/10.1038/srep27806 Text en Copyright © 2016, Macmillan Publishers Limited https://creativecommons.org/licenses/by/4.0/This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) |
spellingShingle | Article Goldgof, Gregory M. Durrant, Jacob D. Ottilie, Sabine Vigil, Edgar Allen, Kenneth E. Gunawan, Felicia Kostylev, Maxim Henderson, Kiersten A. Yang, Jennifer Schenken, Jake LaMonte, Gregory M. Manary, Micah J. Murao, Ayako Nachon, Marie Murray, Rebecca Prescott, Maximo McNamara, Case W. Slayman, Carolyn W. Amaro, Rommie E. Suzuki, Yo Winzeler, Elizabeth A. Comparative chemical genomics reveal that the spiroindolone antimalarial KAE609 (Cipargamin) is a P-type ATPase inhibitor |
title | Comparative chemical genomics reveal that the spiroindolone antimalarial KAE609
(Cipargamin) is a P-type ATPase inhibitor |
title_full | Comparative chemical genomics reveal that the spiroindolone antimalarial KAE609
(Cipargamin) is a P-type ATPase inhibitor |
title_fullStr | Comparative chemical genomics reveal that the spiroindolone antimalarial KAE609
(Cipargamin) is a P-type ATPase inhibitor |
title_full_unstemmed | Comparative chemical genomics reveal that the spiroindolone antimalarial KAE609
(Cipargamin) is a P-type ATPase inhibitor |
title_short | Comparative chemical genomics reveal that the spiroindolone antimalarial KAE609
(Cipargamin) is a P-type ATPase inhibitor |
title_sort | comparative chemical genomics reveal that the spiroindolone antimalarial kae609
(cipargamin) is a p-type atpase inhibitor |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4904242/ https://www.ncbi.nlm.nih.gov/pubmed/27291296 http://dx.doi.org/10.1038/srep27806 |
work_keys_str_mv | AT goldgofgregorym comparativechemicalgenomicsrevealthatthespiroindoloneantimalarialkae609cipargaminisaptypeatpaseinhibitor AT durrantjacobd comparativechemicalgenomicsrevealthatthespiroindoloneantimalarialkae609cipargaminisaptypeatpaseinhibitor AT ottiliesabine comparativechemicalgenomicsrevealthatthespiroindoloneantimalarialkae609cipargaminisaptypeatpaseinhibitor AT vigiledgar comparativechemicalgenomicsrevealthatthespiroindoloneantimalarialkae609cipargaminisaptypeatpaseinhibitor AT allenkennethe comparativechemicalgenomicsrevealthatthespiroindoloneantimalarialkae609cipargaminisaptypeatpaseinhibitor AT gunawanfelicia comparativechemicalgenomicsrevealthatthespiroindoloneantimalarialkae609cipargaminisaptypeatpaseinhibitor AT kostylevmaxim comparativechemicalgenomicsrevealthatthespiroindoloneantimalarialkae609cipargaminisaptypeatpaseinhibitor AT hendersonkierstena comparativechemicalgenomicsrevealthatthespiroindoloneantimalarialkae609cipargaminisaptypeatpaseinhibitor AT yangjennifer comparativechemicalgenomicsrevealthatthespiroindoloneantimalarialkae609cipargaminisaptypeatpaseinhibitor AT schenkenjake comparativechemicalgenomicsrevealthatthespiroindoloneantimalarialkae609cipargaminisaptypeatpaseinhibitor AT lamontegregorym comparativechemicalgenomicsrevealthatthespiroindoloneantimalarialkae609cipargaminisaptypeatpaseinhibitor AT manarymicahj comparativechemicalgenomicsrevealthatthespiroindoloneantimalarialkae609cipargaminisaptypeatpaseinhibitor AT muraoayako comparativechemicalgenomicsrevealthatthespiroindoloneantimalarialkae609cipargaminisaptypeatpaseinhibitor AT nachonmarie comparativechemicalgenomicsrevealthatthespiroindoloneantimalarialkae609cipargaminisaptypeatpaseinhibitor AT murrayrebecca comparativechemicalgenomicsrevealthatthespiroindoloneantimalarialkae609cipargaminisaptypeatpaseinhibitor AT prescottmaximo comparativechemicalgenomicsrevealthatthespiroindoloneantimalarialkae609cipargaminisaptypeatpaseinhibitor AT mcnamaracasew comparativechemicalgenomicsrevealthatthespiroindoloneantimalarialkae609cipargaminisaptypeatpaseinhibitor AT slaymancarolynw comparativechemicalgenomicsrevealthatthespiroindoloneantimalarialkae609cipargaminisaptypeatpaseinhibitor AT amarorommiee comparativechemicalgenomicsrevealthatthespiroindoloneantimalarialkae609cipargaminisaptypeatpaseinhibitor AT suzukiyo comparativechemicalgenomicsrevealthatthespiroindoloneantimalarialkae609cipargaminisaptypeatpaseinhibitor AT winzelerelizabetha comparativechemicalgenomicsrevealthatthespiroindoloneantimalarialkae609cipargaminisaptypeatpaseinhibitor |