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Ultra-short-course and intermittent TB47-containing oral regimens produce stable cure against Buruli ulcer in a murine model and prevent the emergence of resistance for Mycobacterium ulcerans
Buruli ulcer (BU), caused by Mycobacterium ulcerans, is currently treated with rifampin–streptomycin or rifampin–clarithromycin daily for 8 weeks recommended by World Health Organization (WHO). These options are lengthy with severe side effects. A new anti-tuberculosis drug, TB47, targeting QcrB in...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7982501/ https://www.ncbi.nlm.nih.gov/pubmed/33777679 http://dx.doi.org/10.1016/j.apsb.2020.11.007 |
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author | Gao, Yamin Hameed, H.M. Adnan Liu, Yang Guo, Lingmin Fang, Cuiting Tian, Xirong Liu, Zhiyong Wang, Shuai Lu, Zhili Islam, Md Mahmudul Zhang, Tianyu |
author_facet | Gao, Yamin Hameed, H.M. Adnan Liu, Yang Guo, Lingmin Fang, Cuiting Tian, Xirong Liu, Zhiyong Wang, Shuai Lu, Zhili Islam, Md Mahmudul Zhang, Tianyu |
author_sort | Gao, Yamin |
collection | PubMed |
description | Buruli ulcer (BU), caused by Mycobacterium ulcerans, is currently treated with rifampin–streptomycin or rifampin–clarithromycin daily for 8 weeks recommended by World Health Organization (WHO). These options are lengthy with severe side effects. A new anti-tuberculosis drug, TB47, targeting QcrB in cytochrome bc1:aa3 complex is being developed in China. TB47-containing regimens were evaluated in a well-established murine model using an autoluminescent M. ulcerans strain. High-level TB47-resistant spontaneous M. ulcerans mutants were selected and their qcrB genes were sequenced. The in vivo activities of TB47 against both low-level and high-level TB47-resistant mutants were tested in BU murine model. Here, we show that TB47-containing oral 3-drug regimens can completely cure BU in ≤2 weeks for daily use or in ≤3 weeks given twice per week (6 doses in total). All high-level TB47-resistant mutants could only be selected using the low-level mutants which were still sensitive to TB47 in mice. This is the first report of double mutations in QcrB in mycobacteria. In summary, TB47-containing regimens have promise to cure BU highly effectively and prevent the emergence of drug resistance. Novel QcrB mutations found here may guide the potential clinical molecular diagnosis of resistance and the discovery of new drugs against the high-level resistant mutants. |
format | Online Article Text |
id | pubmed-7982501 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
spelling | pubmed-79825012021-03-25 Ultra-short-course and intermittent TB47-containing oral regimens produce stable cure against Buruli ulcer in a murine model and prevent the emergence of resistance for Mycobacterium ulcerans Gao, Yamin Hameed, H.M. Adnan Liu, Yang Guo, Lingmin Fang, Cuiting Tian, Xirong Liu, Zhiyong Wang, Shuai Lu, Zhili Islam, Md Mahmudul Zhang, Tianyu Acta Pharm Sin B Original Article Buruli ulcer (BU), caused by Mycobacterium ulcerans, is currently treated with rifampin–streptomycin or rifampin–clarithromycin daily for 8 weeks recommended by World Health Organization (WHO). These options are lengthy with severe side effects. A new anti-tuberculosis drug, TB47, targeting QcrB in cytochrome bc1:aa3 complex is being developed in China. TB47-containing regimens were evaluated in a well-established murine model using an autoluminescent M. ulcerans strain. High-level TB47-resistant spontaneous M. ulcerans mutants were selected and their qcrB genes were sequenced. The in vivo activities of TB47 against both low-level and high-level TB47-resistant mutants were tested in BU murine model. Here, we show that TB47-containing oral 3-drug regimens can completely cure BU in ≤2 weeks for daily use or in ≤3 weeks given twice per week (6 doses in total). All high-level TB47-resistant mutants could only be selected using the low-level mutants which were still sensitive to TB47 in mice. This is the first report of double mutations in QcrB in mycobacteria. In summary, TB47-containing regimens have promise to cure BU highly effectively and prevent the emergence of drug resistance. Novel QcrB mutations found here may guide the potential clinical molecular diagnosis of resistance and the discovery of new drugs against the high-level resistant mutants. Elsevier 2021-03 2020-11-13 /pmc/articles/PMC7982501/ /pubmed/33777679 http://dx.doi.org/10.1016/j.apsb.2020.11.007 Text en © 2020 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V. http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Original Article Gao, Yamin Hameed, H.M. Adnan Liu, Yang Guo, Lingmin Fang, Cuiting Tian, Xirong Liu, Zhiyong Wang, Shuai Lu, Zhili Islam, Md Mahmudul Zhang, Tianyu Ultra-short-course and intermittent TB47-containing oral regimens produce stable cure against Buruli ulcer in a murine model and prevent the emergence of resistance for Mycobacterium ulcerans |
title | Ultra-short-course and intermittent TB47-containing oral regimens produce stable cure against Buruli ulcer in a murine model and prevent the emergence of resistance for Mycobacterium ulcerans |
title_full | Ultra-short-course and intermittent TB47-containing oral regimens produce stable cure against Buruli ulcer in a murine model and prevent the emergence of resistance for Mycobacterium ulcerans |
title_fullStr | Ultra-short-course and intermittent TB47-containing oral regimens produce stable cure against Buruli ulcer in a murine model and prevent the emergence of resistance for Mycobacterium ulcerans |
title_full_unstemmed | Ultra-short-course and intermittent TB47-containing oral regimens produce stable cure against Buruli ulcer in a murine model and prevent the emergence of resistance for Mycobacterium ulcerans |
title_short | Ultra-short-course and intermittent TB47-containing oral regimens produce stable cure against Buruli ulcer in a murine model and prevent the emergence of resistance for Mycobacterium ulcerans |
title_sort | ultra-short-course and intermittent tb47-containing oral regimens produce stable cure against buruli ulcer in a murine model and prevent the emergence of resistance for mycobacterium ulcerans |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7982501/ https://www.ncbi.nlm.nih.gov/pubmed/33777679 http://dx.doi.org/10.1016/j.apsb.2020.11.007 |
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