Cargando…
A Chemical Genomic Analysis of Decoquinate, a Plasmodium falciparum Cytochrome b Inhibitor
[Image: see text] Decoquinate has single-digit nanomolar activity against in vitro blood stage Plasmodium falciparum parasites, the causative agent of human malaria. In vitro evolution of decoquinate-resistant parasites and subsequent comparative genomic analysis to the drug-sensitive parental strai...
Autores principales: | , , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Chemical Society
2011
|
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3220786/ https://www.ncbi.nlm.nih.gov/pubmed/21866942 http://dx.doi.org/10.1021/cb200105d |
_version_ | 1782216997848743936 |
---|---|
author | Nam, Tae-gyu McNamara, Case W. Bopp, Selina Dharia, Neekesh V. Meister, Stephan Bonamy, Ghislain M. C. Plouffe, David M. Kato, Nobutaka McCormack, Susan Bursulaya, Badry Ke, Hangjun Vaidya, Akhil B. Schultz, Peter G. Winzeler, Elizabeth A. |
author_facet | Nam, Tae-gyu McNamara, Case W. Bopp, Selina Dharia, Neekesh V. Meister, Stephan Bonamy, Ghislain M. C. Plouffe, David M. Kato, Nobutaka McCormack, Susan Bursulaya, Badry Ke, Hangjun Vaidya, Akhil B. Schultz, Peter G. Winzeler, Elizabeth A. |
author_sort | Nam, Tae-gyu |
collection | PubMed |
description | [Image: see text] Decoquinate has single-digit nanomolar activity against in vitro blood stage Plasmodium falciparum parasites, the causative agent of human malaria. In vitro evolution of decoquinate-resistant parasites and subsequent comparative genomic analysis to the drug-sensitive parental strain revealed resistance was conferred by two nonsynonymous single nucleotide polymorphisms in the gene encoding cytochrome b. The resultant amino acid mutations, A122T and Y126C, reside within helix C in the ubiquinol-binding pocket of cytochrome b, an essential subunit of the cytochrome bc(1) complex. As with other cytochrome bc(1) inhibitors, such as atovaquone, decoquinate has low nanomolar activity against in vitro liver stage P. yoelii and provides partial prophylaxis protection when administered to infected mice at 50 mg kg(–1). In addition, transgenic parasites expressing yeast dihydroorotate dehydrogenase are >200-fold less sensitive to decoquinate, which provides additional evidence that this drug inhibits the parasite’s mitochondrial electron transport chain. Importantly, decoquinate exhibits limited cross-resistance to a panel of atovaquone-resistant parasites evolved to harbor various mutations in cytochrome b. The basis for this difference was revealed by molecular docking studies, in which both of these inhibitors were shown to have distinctly different modes of binding within the ubiquinol-binding site of cytochrome b. |
format | Online Article Text |
id | pubmed-3220786 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2011 |
publisher | American Chemical Society |
record_format | MEDLINE/PubMed |
spelling | pubmed-32207862012-08-14 A Chemical Genomic Analysis of Decoquinate, a Plasmodium falciparum Cytochrome b Inhibitor Nam, Tae-gyu McNamara, Case W. Bopp, Selina Dharia, Neekesh V. Meister, Stephan Bonamy, Ghislain M. C. Plouffe, David M. Kato, Nobutaka McCormack, Susan Bursulaya, Badry Ke, Hangjun Vaidya, Akhil B. Schultz, Peter G. Winzeler, Elizabeth A. ACS Chem Biol [Image: see text] Decoquinate has single-digit nanomolar activity against in vitro blood stage Plasmodium falciparum parasites, the causative agent of human malaria. In vitro evolution of decoquinate-resistant parasites and subsequent comparative genomic analysis to the drug-sensitive parental strain revealed resistance was conferred by two nonsynonymous single nucleotide polymorphisms in the gene encoding cytochrome b. The resultant amino acid mutations, A122T and Y126C, reside within helix C in the ubiquinol-binding pocket of cytochrome b, an essential subunit of the cytochrome bc(1) complex. As with other cytochrome bc(1) inhibitors, such as atovaquone, decoquinate has low nanomolar activity against in vitro liver stage P. yoelii and provides partial prophylaxis protection when administered to infected mice at 50 mg kg(–1). In addition, transgenic parasites expressing yeast dihydroorotate dehydrogenase are >200-fold less sensitive to decoquinate, which provides additional evidence that this drug inhibits the parasite’s mitochondrial electron transport chain. Importantly, decoquinate exhibits limited cross-resistance to a panel of atovaquone-resistant parasites evolved to harbor various mutations in cytochrome b. The basis for this difference was revealed by molecular docking studies, in which both of these inhibitors were shown to have distinctly different modes of binding within the ubiquinol-binding site of cytochrome b. American Chemical Society 2011-08-25 2011-11-18 /pmc/articles/PMC3220786/ /pubmed/21866942 http://dx.doi.org/10.1021/cb200105d Text en Copyright © 2011 American Chemical Society http://pubs.acs.org This is an open-access article distributed under the ACS AuthorChoice Terms & Conditions. Any use of this article, must conform to the terms of that license which are available at http://pubs.acs.org. |
spellingShingle | Nam, Tae-gyu McNamara, Case W. Bopp, Selina Dharia, Neekesh V. Meister, Stephan Bonamy, Ghislain M. C. Plouffe, David M. Kato, Nobutaka McCormack, Susan Bursulaya, Badry Ke, Hangjun Vaidya, Akhil B. Schultz, Peter G. Winzeler, Elizabeth A. A Chemical Genomic Analysis of Decoquinate, a Plasmodium falciparum Cytochrome b Inhibitor |
title | A Chemical Genomic Analysis of Decoquinate, a Plasmodium falciparum Cytochrome b Inhibitor |
title_full | A Chemical Genomic Analysis of Decoquinate, a Plasmodium falciparum Cytochrome b Inhibitor |
title_fullStr | A Chemical Genomic Analysis of Decoquinate, a Plasmodium falciparum Cytochrome b Inhibitor |
title_full_unstemmed | A Chemical Genomic Analysis of Decoquinate, a Plasmodium falciparum Cytochrome b Inhibitor |
title_short | A Chemical Genomic Analysis of Decoquinate, a Plasmodium falciparum Cytochrome b Inhibitor |
title_sort | chemical genomic analysis of decoquinate, a plasmodium falciparum cytochrome b inhibitor |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3220786/ https://www.ncbi.nlm.nih.gov/pubmed/21866942 http://dx.doi.org/10.1021/cb200105d |
work_keys_str_mv | AT namtaegyu achemicalgenomicanalysisofdecoquinateaplasmodiumfalciparumcytochromebinhibitor AT mcnamaracasew achemicalgenomicanalysisofdecoquinateaplasmodiumfalciparumcytochromebinhibitor AT boppselina achemicalgenomicanalysisofdecoquinateaplasmodiumfalciparumcytochromebinhibitor AT dharianeekeshv achemicalgenomicanalysisofdecoquinateaplasmodiumfalciparumcytochromebinhibitor AT meisterstephan achemicalgenomicanalysisofdecoquinateaplasmodiumfalciparumcytochromebinhibitor AT bonamyghislainmc achemicalgenomicanalysisofdecoquinateaplasmodiumfalciparumcytochromebinhibitor AT plouffedavidm achemicalgenomicanalysisofdecoquinateaplasmodiumfalciparumcytochromebinhibitor AT katonobutaka achemicalgenomicanalysisofdecoquinateaplasmodiumfalciparumcytochromebinhibitor AT mccormacksusan achemicalgenomicanalysisofdecoquinateaplasmodiumfalciparumcytochromebinhibitor AT bursulayabadry achemicalgenomicanalysisofdecoquinateaplasmodiumfalciparumcytochromebinhibitor AT kehangjun achemicalgenomicanalysisofdecoquinateaplasmodiumfalciparumcytochromebinhibitor AT vaidyaakhilb achemicalgenomicanalysisofdecoquinateaplasmodiumfalciparumcytochromebinhibitor AT schultzpeterg achemicalgenomicanalysisofdecoquinateaplasmodiumfalciparumcytochromebinhibitor AT winzelerelizabetha achemicalgenomicanalysisofdecoquinateaplasmodiumfalciparumcytochromebinhibitor AT namtaegyu chemicalgenomicanalysisofdecoquinateaplasmodiumfalciparumcytochromebinhibitor AT mcnamaracasew chemicalgenomicanalysisofdecoquinateaplasmodiumfalciparumcytochromebinhibitor AT boppselina chemicalgenomicanalysisofdecoquinateaplasmodiumfalciparumcytochromebinhibitor AT dharianeekeshv chemicalgenomicanalysisofdecoquinateaplasmodiumfalciparumcytochromebinhibitor AT meisterstephan chemicalgenomicanalysisofdecoquinateaplasmodiumfalciparumcytochromebinhibitor AT bonamyghislainmc chemicalgenomicanalysisofdecoquinateaplasmodiumfalciparumcytochromebinhibitor AT plouffedavidm chemicalgenomicanalysisofdecoquinateaplasmodiumfalciparumcytochromebinhibitor AT katonobutaka chemicalgenomicanalysisofdecoquinateaplasmodiumfalciparumcytochromebinhibitor AT mccormacksusan chemicalgenomicanalysisofdecoquinateaplasmodiumfalciparumcytochromebinhibitor AT bursulayabadry chemicalgenomicanalysisofdecoquinateaplasmodiumfalciparumcytochromebinhibitor AT kehangjun chemicalgenomicanalysisofdecoquinateaplasmodiumfalciparumcytochromebinhibitor AT vaidyaakhilb chemicalgenomicanalysisofdecoquinateaplasmodiumfalciparumcytochromebinhibitor AT schultzpeterg chemicalgenomicanalysisofdecoquinateaplasmodiumfalciparumcytochromebinhibitor AT winzelerelizabetha chemicalgenomicanalysisofdecoquinateaplasmodiumfalciparumcytochromebinhibitor |