Fragment-Sized EthR Inhibitors Exhibit Exceptionally Strong Ethionamide Boosting Effect in Whole-Cell Mycobacterium tuberculosis Assays

[Image: see text] Small-molecule inhibitors of the mycobacterial transcriptional repressor EthR have previously been shown to act as boosters of the second-line antituberculosis drug ethionamide. Fragment-based drug discovery approaches have been used in the past to make highly potent EthR inhibitor...

Descripción completa

Detalles Bibliográficos
Autores principales: Nikiforov, Petar O., Blaszczyk, Michal, Surade, Sachin, Boshoff, Helena I., Sajid, Andaleeb, Delorme, Vincent, Deboosere, Nathalie, Brodin, Priscille, Baulard, Alain R., Barry, Clifton E., Blundell, Tom L., Abell, Chris
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2017
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5474694/
https://www.ncbi.nlm.nih.gov/pubmed/28314097
http://dx.doi.org/10.1021/acschembio.7b00091
_version_ 1783244499640647680
author Nikiforov, Petar O.
Blaszczyk, Michal
Surade, Sachin
Boshoff, Helena I.
Sajid, Andaleeb
Delorme, Vincent
Deboosere, Nathalie
Brodin, Priscille
Baulard, Alain R.
Barry, Clifton E.
Blundell, Tom L.
Abell, Chris
author_facet Nikiforov, Petar O.
Blaszczyk, Michal
Surade, Sachin
Boshoff, Helena I.
Sajid, Andaleeb
Delorme, Vincent
Deboosere, Nathalie
Brodin, Priscille
Baulard, Alain R.
Barry, Clifton E.
Blundell, Tom L.
Abell, Chris
author_sort Nikiforov, Petar O.
collection PubMed
description [Image: see text] Small-molecule inhibitors of the mycobacterial transcriptional repressor EthR have previously been shown to act as boosters of the second-line antituberculosis drug ethionamide. Fragment-based drug discovery approaches have been used in the past to make highly potent EthR inhibitors with ethionamide boosting activity both in vitro and ex vivo. Herein, we report the development of fragment-sized EthR ligands with nanomolar minimum effective concentration values for boosting the ethionamide activity in Mycobacterium tuberculosis whole-cell assays.
format Online
Article
Text
id pubmed-5474694
institution National Center for Biotechnology Information
language English
publishDate 2017
publisher American Chemical Society
record_format MEDLINE/PubMed
spelling pubmed-54746942017-06-21 Fragment-Sized EthR Inhibitors Exhibit Exceptionally Strong Ethionamide Boosting Effect in Whole-Cell Mycobacterium tuberculosis Assays Nikiforov, Petar O. Blaszczyk, Michal Surade, Sachin Boshoff, Helena I. Sajid, Andaleeb Delorme, Vincent Deboosere, Nathalie Brodin, Priscille Baulard, Alain R. Barry, Clifton E. Blundell, Tom L. Abell, Chris ACS Chem Biol [Image: see text] Small-molecule inhibitors of the mycobacterial transcriptional repressor EthR have previously been shown to act as boosters of the second-line antituberculosis drug ethionamide. Fragment-based drug discovery approaches have been used in the past to make highly potent EthR inhibitors with ethionamide boosting activity both in vitro and ex vivo. Herein, we report the development of fragment-sized EthR ligands with nanomolar minimum effective concentration values for boosting the ethionamide activity in Mycobacterium tuberculosis whole-cell assays. American Chemical Society 2017-03-17 2017-05-19 /pmc/articles/PMC5474694/ /pubmed/28314097 http://dx.doi.org/10.1021/acschembio.7b00091 Text en Copyright © 2017 American Chemical Society This is an open access article published under a Creative Commons Attribution (CC-BY) License (http://pubs.acs.org/page/policy/authorchoice_ccby_termsofuse.html) , which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited.
spellingShingle Nikiforov, Petar O.
Blaszczyk, Michal
Surade, Sachin
Boshoff, Helena I.
Sajid, Andaleeb
Delorme, Vincent
Deboosere, Nathalie
Brodin, Priscille
Baulard, Alain R.
Barry, Clifton E.
Blundell, Tom L.
Abell, Chris
Fragment-Sized EthR Inhibitors Exhibit Exceptionally Strong Ethionamide Boosting Effect in Whole-Cell Mycobacterium tuberculosis Assays
title Fragment-Sized EthR Inhibitors Exhibit Exceptionally Strong Ethionamide Boosting Effect in Whole-Cell Mycobacterium tuberculosis Assays
title_full Fragment-Sized EthR Inhibitors Exhibit Exceptionally Strong Ethionamide Boosting Effect in Whole-Cell Mycobacterium tuberculosis Assays
title_fullStr Fragment-Sized EthR Inhibitors Exhibit Exceptionally Strong Ethionamide Boosting Effect in Whole-Cell Mycobacterium tuberculosis Assays
title_full_unstemmed Fragment-Sized EthR Inhibitors Exhibit Exceptionally Strong Ethionamide Boosting Effect in Whole-Cell Mycobacterium tuberculosis Assays
title_short Fragment-Sized EthR Inhibitors Exhibit Exceptionally Strong Ethionamide Boosting Effect in Whole-Cell Mycobacterium tuberculosis Assays
title_sort fragment-sized ethr inhibitors exhibit exceptionally strong ethionamide boosting effect in whole-cell mycobacterium tuberculosis assays
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5474694/
https://www.ncbi.nlm.nih.gov/pubmed/28314097
http://dx.doi.org/10.1021/acschembio.7b00091
work_keys_str_mv AT nikiforovpetaro fragmentsizedethrinhibitorsexhibitexceptionallystrongethionamideboostingeffectinwholecellmycobacteriumtuberculosisassays
AT blaszczykmichal fragmentsizedethrinhibitorsexhibitexceptionallystrongethionamideboostingeffectinwholecellmycobacteriumtuberculosisassays
AT suradesachin fragmentsizedethrinhibitorsexhibitexceptionallystrongethionamideboostingeffectinwholecellmycobacteriumtuberculosisassays
AT boshoffhelenai fragmentsizedethrinhibitorsexhibitexceptionallystrongethionamideboostingeffectinwholecellmycobacteriumtuberculosisassays
AT sajidandaleeb fragmentsizedethrinhibitorsexhibitexceptionallystrongethionamideboostingeffectinwholecellmycobacteriumtuberculosisassays
AT delormevincent fragmentsizedethrinhibitorsexhibitexceptionallystrongethionamideboostingeffectinwholecellmycobacteriumtuberculosisassays
AT debooserenathalie fragmentsizedethrinhibitorsexhibitexceptionallystrongethionamideboostingeffectinwholecellmycobacteriumtuberculosisassays
AT brodinpriscille fragmentsizedethrinhibitorsexhibitexceptionallystrongethionamideboostingeffectinwholecellmycobacteriumtuberculosisassays
AT baulardalainr fragmentsizedethrinhibitorsexhibitexceptionallystrongethionamideboostingeffectinwholecellmycobacteriumtuberculosisassays
AT barrycliftone fragmentsizedethrinhibitorsexhibitexceptionallystrongethionamideboostingeffectinwholecellmycobacteriumtuberculosisassays
AT blundelltoml fragmentsizedethrinhibitorsexhibitexceptionallystrongethionamideboostingeffectinwholecellmycobacteriumtuberculosisassays
AT abellchris fragmentsizedethrinhibitorsexhibitexceptionallystrongethionamideboostingeffectinwholecellmycobacteriumtuberculosisassays

Ejemplares similares