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A novel protein kinase inhibitor IMB-YH-8 with anti-tuberculosis activity
Protein kinase B (PknB) is one of the Mycobacterium tuberculosis serine/threonine protein kinases and has an essential role in sustaining mycobacterial growth. Here, we identified and characterized a novel small molecule compound named IMB-YH-8 that inhibited PknB and served as anti-mycobacteria lea...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5506005/ https://www.ncbi.nlm.nih.gov/pubmed/28698545 http://dx.doi.org/10.1038/s41598-017-04108-7 |
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author | Xu, Jian Wang, Ju-xian Zhou, Jin-ming Xu, Chang-liang Huang, Bin Xing, Yun Wang, Bin Luo, Rui Wang, Yu-cheng You, Xue-fu Lu, Yu Yu, Li-yan |
author_facet | Xu, Jian Wang, Ju-xian Zhou, Jin-ming Xu, Chang-liang Huang, Bin Xing, Yun Wang, Bin Luo, Rui Wang, Yu-cheng You, Xue-fu Lu, Yu Yu, Li-yan |
author_sort | Xu, Jian |
collection | PubMed |
description | Protein kinase B (PknB) is one of the Mycobacterium tuberculosis serine/threonine protein kinases and has an essential role in sustaining mycobacterial growth. Here, we identified and characterized a novel small molecule compound named IMB-YH-8 that inhibited PknB and served as anti-mycobacteria lead compound. IMB-YH-8 inhibited PknB auto-phosphorylation and the phosphorylation of GarA by PknB in a dose-dependent manner. The compound did not inhibit human Akt1 or other serine/threonine kinases in M. tuberculosis except for the highly homologous PknA. IMB-YH-8 bound to PknB with a moderate affinity. Molecular docking revealed that IMB-YH-8 interacts with the catalytic domain of PknB. Observations of electron microscopy showed that IMB-YH-8 changed the morphology of H37Rv and disrupted the cell wall. The differential transcriptional response of M. tuberculosis to IMB-YH-8 revealed changes in SigH regulatory pathways modulated by PknB. Notably IMB-YH-8 not only potently inhibited drug-sensitive and multidrug-resistant clinical isolates but also exhibited a dose dependent inhibition of intracellular M. tuberculosis. Taken together, these in vitro data demonstrate that IMB-YH-8 is a novel inhibitor of PknB, which potently prevents growth of M. tuberculosis. It is as yet unclear whether inhibition of PknA contributes to the anti-tubercular action of IMB-YH-8. |
format | Online Article Text |
id | pubmed-5506005 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-55060052017-07-13 A novel protein kinase inhibitor IMB-YH-8 with anti-tuberculosis activity Xu, Jian Wang, Ju-xian Zhou, Jin-ming Xu, Chang-liang Huang, Bin Xing, Yun Wang, Bin Luo, Rui Wang, Yu-cheng You, Xue-fu Lu, Yu Yu, Li-yan Sci Rep Article Protein kinase B (PknB) is one of the Mycobacterium tuberculosis serine/threonine protein kinases and has an essential role in sustaining mycobacterial growth. Here, we identified and characterized a novel small molecule compound named IMB-YH-8 that inhibited PknB and served as anti-mycobacteria lead compound. IMB-YH-8 inhibited PknB auto-phosphorylation and the phosphorylation of GarA by PknB in a dose-dependent manner. The compound did not inhibit human Akt1 or other serine/threonine kinases in M. tuberculosis except for the highly homologous PknA. IMB-YH-8 bound to PknB with a moderate affinity. Molecular docking revealed that IMB-YH-8 interacts with the catalytic domain of PknB. Observations of electron microscopy showed that IMB-YH-8 changed the morphology of H37Rv and disrupted the cell wall. The differential transcriptional response of M. tuberculosis to IMB-YH-8 revealed changes in SigH regulatory pathways modulated by PknB. Notably IMB-YH-8 not only potently inhibited drug-sensitive and multidrug-resistant clinical isolates but also exhibited a dose dependent inhibition of intracellular M. tuberculosis. Taken together, these in vitro data demonstrate that IMB-YH-8 is a novel inhibitor of PknB, which potently prevents growth of M. tuberculosis. It is as yet unclear whether inhibition of PknA contributes to the anti-tubercular action of IMB-YH-8. Nature Publishing Group UK 2017-07-11 /pmc/articles/PMC5506005/ /pubmed/28698545 http://dx.doi.org/10.1038/s41598-017-04108-7 Text en © The Author(s) 2017 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 Xu, Jian Wang, Ju-xian Zhou, Jin-ming Xu, Chang-liang Huang, Bin Xing, Yun Wang, Bin Luo, Rui Wang, Yu-cheng You, Xue-fu Lu, Yu Yu, Li-yan A novel protein kinase inhibitor IMB-YH-8 with anti-tuberculosis activity |
title | A novel protein kinase inhibitor IMB-YH-8 with anti-tuberculosis activity |
title_full | A novel protein kinase inhibitor IMB-YH-8 with anti-tuberculosis activity |
title_fullStr | A novel protein kinase inhibitor IMB-YH-8 with anti-tuberculosis activity |
title_full_unstemmed | A novel protein kinase inhibitor IMB-YH-8 with anti-tuberculosis activity |
title_short | A novel protein kinase inhibitor IMB-YH-8 with anti-tuberculosis activity |
title_sort | novel protein kinase inhibitor imb-yh-8 with anti-tuberculosis activity |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5506005/ https://www.ncbi.nlm.nih.gov/pubmed/28698545 http://dx.doi.org/10.1038/s41598-017-04108-7 |
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