Cargando…
Screening and Development of New Inhibitors of FtsZ from M. Tuberculosis
A variety of commercial analogs and a newer series of Sulindac derivatives were screened for inhibition of M. tuberculosis (Mtb) in vitro and specifically as inhibitors of the essential mycobacterial tubulin homolog, FtsZ. Due to the ease of preparing diverse analogs and a favorable in vivo pharmaco...
Autores principales: | , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2016
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5074515/ https://www.ncbi.nlm.nih.gov/pubmed/27768711 http://dx.doi.org/10.1371/journal.pone.0164100 |
_version_ | 1782461735444152320 |
---|---|
author | Mathew, Bini Hobrath, Judith Varady Ross, Larry Connelly, Michele C. Lofton, Hava Rajagopalan, Malini Guy, R. Kiplin Reynolds, Robert C. |
author_facet | Mathew, Bini Hobrath, Judith Varady Ross, Larry Connelly, Michele C. Lofton, Hava Rajagopalan, Malini Guy, R. Kiplin Reynolds, Robert C. |
author_sort | Mathew, Bini |
collection | PubMed |
description | A variety of commercial analogs and a newer series of Sulindac derivatives were screened for inhibition of M. tuberculosis (Mtb) in vitro and specifically as inhibitors of the essential mycobacterial tubulin homolog, FtsZ. Due to the ease of preparing diverse analogs and a favorable in vivo pharmacokinetic and toxicity profile of a representative analog, the Sulindac scaffold may be useful for further development against Mtb with respect to in vitro bacterial growth inhibition and selective activity for Mtb FtsZ versus mammalian tubulin. Further discovery efforts will require separating reported mammalian cell activity from both antibacterial activity and inhibition of Mtb FtsZ. Modeling studies suggest that these analogs bind in a specific region of the Mtb FtsZ polymer that differs from human tubulin and, in combination with a pharmacophore model presented herein, future hybrid analogs of the reported active molecules that more efficiently bind in this pocket may improve antibacterial activity while improving other drug characteristics. |
format | Online Article Text |
id | pubmed-5074515 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-50745152016-11-04 Screening and Development of New Inhibitors of FtsZ from M. Tuberculosis Mathew, Bini Hobrath, Judith Varady Ross, Larry Connelly, Michele C. Lofton, Hava Rajagopalan, Malini Guy, R. Kiplin Reynolds, Robert C. PLoS One Research Article A variety of commercial analogs and a newer series of Sulindac derivatives were screened for inhibition of M. tuberculosis (Mtb) in vitro and specifically as inhibitors of the essential mycobacterial tubulin homolog, FtsZ. Due to the ease of preparing diverse analogs and a favorable in vivo pharmacokinetic and toxicity profile of a representative analog, the Sulindac scaffold may be useful for further development against Mtb with respect to in vitro bacterial growth inhibition and selective activity for Mtb FtsZ versus mammalian tubulin. Further discovery efforts will require separating reported mammalian cell activity from both antibacterial activity and inhibition of Mtb FtsZ. Modeling studies suggest that these analogs bind in a specific region of the Mtb FtsZ polymer that differs from human tubulin and, in combination with a pharmacophore model presented herein, future hybrid analogs of the reported active molecules that more efficiently bind in this pocket may improve antibacterial activity while improving other drug characteristics. Public Library of Science 2016-10-21 /pmc/articles/PMC5074515/ /pubmed/27768711 http://dx.doi.org/10.1371/journal.pone.0164100 Text en © 2016 Mathew et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Mathew, Bini Hobrath, Judith Varady Ross, Larry Connelly, Michele C. Lofton, Hava Rajagopalan, Malini Guy, R. Kiplin Reynolds, Robert C. Screening and Development of New Inhibitors of FtsZ from M. Tuberculosis |
title | Screening and Development of New Inhibitors of FtsZ from M. Tuberculosis |
title_full | Screening and Development of New Inhibitors of FtsZ from M. Tuberculosis |
title_fullStr | Screening and Development of New Inhibitors of FtsZ from M. Tuberculosis |
title_full_unstemmed | Screening and Development of New Inhibitors of FtsZ from M. Tuberculosis |
title_short | Screening and Development of New Inhibitors of FtsZ from M. Tuberculosis |
title_sort | screening and development of new inhibitors of ftsz from m. tuberculosis |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5074515/ https://www.ncbi.nlm.nih.gov/pubmed/27768711 http://dx.doi.org/10.1371/journal.pone.0164100 |
work_keys_str_mv | AT mathewbini screeninganddevelopmentofnewinhibitorsofftszfrommtuberculosis AT hobrathjudithvarady screeninganddevelopmentofnewinhibitorsofftszfrommtuberculosis AT rosslarry screeninganddevelopmentofnewinhibitorsofftszfrommtuberculosis AT connellymichelec screeninganddevelopmentofnewinhibitorsofftszfrommtuberculosis AT loftonhava screeninganddevelopmentofnewinhibitorsofftszfrommtuberculosis AT rajagopalanmalini screeninganddevelopmentofnewinhibitorsofftszfrommtuberculosis AT guyrkiplin screeninganddevelopmentofnewinhibitorsofftszfrommtuberculosis AT reynoldsrobertc screeninganddevelopmentofnewinhibitorsofftszfrommtuberculosis |