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The compound TB47 is highly bactericidal against Mycobacterium ulcerans in a Buruli ulcer mouse model
Buruli ulcer (BU) is an emerging infectious disease that causes disfiguring skin ulcers. The causative agent, Mycobacterium ulcerans, secretes toxin called mycolactone that triggers inflammation and immunopathology. Existing treatments are lengthy and consist of drugs developed for tuberculosis. Her...
Autores principales: | , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6355801/ https://www.ncbi.nlm.nih.gov/pubmed/30705268 http://dx.doi.org/10.1038/s41467-019-08464-y |
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author | Liu, Yang Gao, Yamin Liu, Jianxiong Tan, Yaoju Liu, Zhiyong Chhotaray, Chiranjibi Jiang, Huofeng Lu, Zhili Chiwala, Gift Wang, Shuai Makafe, Gaelle Islam, Md Mahmudul Hameed, H. M. Adnan Cai, Xingshan Wang, Changwei Li, Xinjie Tan, Shouyong Zhang, Tianyu |
author_facet | Liu, Yang Gao, Yamin Liu, Jianxiong Tan, Yaoju Liu, Zhiyong Chhotaray, Chiranjibi Jiang, Huofeng Lu, Zhili Chiwala, Gift Wang, Shuai Makafe, Gaelle Islam, Md Mahmudul Hameed, H. M. Adnan Cai, Xingshan Wang, Changwei Li, Xinjie Tan, Shouyong Zhang, Tianyu |
author_sort | Liu, Yang |
collection | PubMed |
description | Buruli ulcer (BU) is an emerging infectious disease that causes disfiguring skin ulcers. The causative agent, Mycobacterium ulcerans, secretes toxin called mycolactone that triggers inflammation and immunopathology. Existing treatments are lengthy and consist of drugs developed for tuberculosis. Here, we report that a pyrazolo[1,5-a]pyridine-3-carboxamide, TB47, is highly bactericidal against M. ulcerans both in vitro and in vivo. In the validated mouse model of BU, TB47 alone reduces M. ulcerans burden in mouse footpads by more than 2.5 log(10) CFU compared to the standard BU treatment regimen recommended by the WHO. We show that mutations of ubiquinol-cytochrome C reductase cytochrome subunit B confer resistance to TB47 and the dissimilarity of CydABs from different mycobacteria may account for their differences in susceptibility to TB47. TB47 is highly potent against M. ulcerans and possesses desirable pharmacological attributes and low toxicity that warrant further assessment of this agent for treatment of BU. |
format | Online Article Text |
id | pubmed-6355801 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-63558012019-02-04 The compound TB47 is highly bactericidal against Mycobacterium ulcerans in a Buruli ulcer mouse model Liu, Yang Gao, Yamin Liu, Jianxiong Tan, Yaoju Liu, Zhiyong Chhotaray, Chiranjibi Jiang, Huofeng Lu, Zhili Chiwala, Gift Wang, Shuai Makafe, Gaelle Islam, Md Mahmudul Hameed, H. M. Adnan Cai, Xingshan Wang, Changwei Li, Xinjie Tan, Shouyong Zhang, Tianyu Nat Commun Article Buruli ulcer (BU) is an emerging infectious disease that causes disfiguring skin ulcers. The causative agent, Mycobacterium ulcerans, secretes toxin called mycolactone that triggers inflammation and immunopathology. Existing treatments are lengthy and consist of drugs developed for tuberculosis. Here, we report that a pyrazolo[1,5-a]pyridine-3-carboxamide, TB47, is highly bactericidal against M. ulcerans both in vitro and in vivo. In the validated mouse model of BU, TB47 alone reduces M. ulcerans burden in mouse footpads by more than 2.5 log(10) CFU compared to the standard BU treatment regimen recommended by the WHO. We show that mutations of ubiquinol-cytochrome C reductase cytochrome subunit B confer resistance to TB47 and the dissimilarity of CydABs from different mycobacteria may account for their differences in susceptibility to TB47. TB47 is highly potent against M. ulcerans and possesses desirable pharmacological attributes and low toxicity that warrant further assessment of this agent for treatment of BU. Nature Publishing Group UK 2019-01-31 /pmc/articles/PMC6355801/ /pubmed/30705268 http://dx.doi.org/10.1038/s41467-019-08464-y Text en © The Author(s) 2019 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 Liu, Yang Gao, Yamin Liu, Jianxiong Tan, Yaoju Liu, Zhiyong Chhotaray, Chiranjibi Jiang, Huofeng Lu, Zhili Chiwala, Gift Wang, Shuai Makafe, Gaelle Islam, Md Mahmudul Hameed, H. M. Adnan Cai, Xingshan Wang, Changwei Li, Xinjie Tan, Shouyong Zhang, Tianyu The compound TB47 is highly bactericidal against Mycobacterium ulcerans in a Buruli ulcer mouse model |
title | The compound TB47 is highly bactericidal against Mycobacterium ulcerans in a Buruli ulcer mouse model |
title_full | The compound TB47 is highly bactericidal against Mycobacterium ulcerans in a Buruli ulcer mouse model |
title_fullStr | The compound TB47 is highly bactericidal against Mycobacterium ulcerans in a Buruli ulcer mouse model |
title_full_unstemmed | The compound TB47 is highly bactericidal against Mycobacterium ulcerans in a Buruli ulcer mouse model |
title_short | The compound TB47 is highly bactericidal against Mycobacterium ulcerans in a Buruli ulcer mouse model |
title_sort | compound tb47 is highly bactericidal against mycobacterium ulcerans in a buruli ulcer mouse model |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6355801/ https://www.ncbi.nlm.nih.gov/pubmed/30705268 http://dx.doi.org/10.1038/s41467-019-08464-y |
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