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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2021
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.
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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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