Cargando…
The molecular basis of pyrazinamide activity on Mycobacterium tuberculosis PanD
Pyrazinamide has been a mainstay in the multidrug regimens used to treat tuberculosis. It is active against the persistent, non-replicating mycobacteria responsible for the protracted therapy required to cure tuberculosis. Pyrazinamide is a pro-drug that is converted into pyrazinoic acid (POA) by py...
Autores principales: | , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2020
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6969166/ https://www.ncbi.nlm.nih.gov/pubmed/31953389 http://dx.doi.org/10.1038/s41467-019-14238-3 |
_version_ | 1783489284014080000 |
---|---|
author | Sun, Qingan Li, Xiaojun Perez, Lisa M. Shi, Wanliang Zhang, Ying Sacchettini, James C. |
author_facet | Sun, Qingan Li, Xiaojun Perez, Lisa M. Shi, Wanliang Zhang, Ying Sacchettini, James C. |
author_sort | Sun, Qingan |
collection | PubMed |
description | Pyrazinamide has been a mainstay in the multidrug regimens used to treat tuberculosis. It is active against the persistent, non-replicating mycobacteria responsible for the protracted therapy required to cure tuberculosis. Pyrazinamide is a pro-drug that is converted into pyrazinoic acid (POA) by pyrazinamidase, however, the exact target of the drug has been difficult to determine. Here we show the enzyme PanD binds POA in its active site in a manner consistent with competitive inhibition. The active site is not directly accessible to the inhibitor, suggesting the protein must undergo a conformational change to bind the inhibitor. This is consistent with the slow binding kinetics we determined for POA. Drug-resistant mutations cluster near loops that lay on top of the active site. These resistant mutants show reduced affinity and residence time of POA consistent with a model where resistance occurs by destabilizing the closed conformation of the active site. |
format | Online Article Text |
id | pubmed-6969166 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-69691662020-01-21 The molecular basis of pyrazinamide activity on Mycobacterium tuberculosis PanD Sun, Qingan Li, Xiaojun Perez, Lisa M. Shi, Wanliang Zhang, Ying Sacchettini, James C. Nat Commun Article Pyrazinamide has been a mainstay in the multidrug regimens used to treat tuberculosis. It is active against the persistent, non-replicating mycobacteria responsible for the protracted therapy required to cure tuberculosis. Pyrazinamide is a pro-drug that is converted into pyrazinoic acid (POA) by pyrazinamidase, however, the exact target of the drug has been difficult to determine. Here we show the enzyme PanD binds POA in its active site in a manner consistent with competitive inhibition. The active site is not directly accessible to the inhibitor, suggesting the protein must undergo a conformational change to bind the inhibitor. This is consistent with the slow binding kinetics we determined for POA. Drug-resistant mutations cluster near loops that lay on top of the active site. These resistant mutants show reduced affinity and residence time of POA consistent with a model where resistance occurs by destabilizing the closed conformation of the active site. Nature Publishing Group UK 2020-01-17 /pmc/articles/PMC6969166/ /pubmed/31953389 http://dx.doi.org/10.1038/s41467-019-14238-3 Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Sun, Qingan Li, Xiaojun Perez, Lisa M. Shi, Wanliang Zhang, Ying Sacchettini, James C. The molecular basis of pyrazinamide activity on Mycobacterium tuberculosis PanD |
title | The molecular basis of pyrazinamide activity on Mycobacterium tuberculosis PanD |
title_full | The molecular basis of pyrazinamide activity on Mycobacterium tuberculosis PanD |
title_fullStr | The molecular basis of pyrazinamide activity on Mycobacterium tuberculosis PanD |
title_full_unstemmed | The molecular basis of pyrazinamide activity on Mycobacterium tuberculosis PanD |
title_short | The molecular basis of pyrazinamide activity on Mycobacterium tuberculosis PanD |
title_sort | molecular basis of pyrazinamide activity on mycobacterium tuberculosis pand |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6969166/ https://www.ncbi.nlm.nih.gov/pubmed/31953389 http://dx.doi.org/10.1038/s41467-019-14238-3 |
work_keys_str_mv | AT sunqingan themolecularbasisofpyrazinamideactivityonmycobacteriumtuberculosispand AT lixiaojun themolecularbasisofpyrazinamideactivityonmycobacteriumtuberculosispand AT perezlisam themolecularbasisofpyrazinamideactivityonmycobacteriumtuberculosispand AT shiwanliang themolecularbasisofpyrazinamideactivityonmycobacteriumtuberculosispand AT zhangying themolecularbasisofpyrazinamideactivityonmycobacteriumtuberculosispand AT sacchettinijamesc themolecularbasisofpyrazinamideactivityonmycobacteriumtuberculosispand AT sunqingan molecularbasisofpyrazinamideactivityonmycobacteriumtuberculosispand AT lixiaojun molecularbasisofpyrazinamideactivityonmycobacteriumtuberculosispand AT perezlisam molecularbasisofpyrazinamideactivityonmycobacteriumtuberculosispand AT shiwanliang molecularbasisofpyrazinamideactivityonmycobacteriumtuberculosispand AT zhangying molecularbasisofpyrazinamideactivityonmycobacteriumtuberculosispand AT sacchettinijamesc molecularbasisofpyrazinamideactivityonmycobacteriumtuberculosispand |