Original articles
Yamin Gao, H. M. Adnan Hameed, Yang Liu, Lingmin Guo, Cuiting Fang, Xirong Tian, Zhiyong Liu, Shuai Wang, Zhili Lu, Md Mahmudul Islam, Tianyu Zhang. 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[J]. Acta Pharmaceutica Sinica B, 2021, 11(3): 738-749

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
Yamin Gaoa,b,c, H. M. Adnan Hameeda,b,c, Yang Liua,d, Lingmin Guoa,b,c, Cuiting Fanga,b,c, Xirong Tiana,d, Zhiyong Liua,c, Shuai Wanga,b,c, Zhili Lua,c, Md Mahmudul Islama,b,c, Tianyu Zhanga,b,c
a State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China;
b University of Chinese Academy of Sciences, Beijing 100049, China;
c Guangdong-Hong Kong-Macao Joint Laboratory of Respiratory Infectious Diseases, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China;
d Institute of Physical Science and Information Technology, Anhui University, Hefei 230601, China
Buruli ulcer (BU), caused by Mycobacterium ulcerans, is currently treated with rifampin—estreptomycin or rifampin—eclarithromycin 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.
Key words:    Mycobacterium ulcerans    Buruli ulcer    Electron transport chain    QcrB    Chemotherapy    TB47    Drug resistance    Clofazimine   
Received: 2020-06-09     Revised: 2020-09-01
DOI: 10.1016/j.apsb.2020.11.007
Funds: We thank Professor Eric L. Nuermberger at Johns Hopkins University (USA) for providing us M. ulcerans strains as kind gifts for our study. We thank Dr. Xiantao Zhang, the board chairman of Guangzhou Eggbio Co. Ltd. for providing us with TB47 for the experiments. We thank the UCAS Postdoctoral Fellowship (to Hameed HMA) and CAS-TWAS President’s Ph.D. Fellowship Program (to Islam MM) for international students. Tianyu Zhang received Science and Technology Innovation Leader of Guangdong Province (2016TX03R095, China). This work was supported by the National Mega-Project of China for Innovative Drugs (2019ZX09721001-003-003), the Chinese Academy of Sciences grant (154144KYSB20190005, China), the Key-Area Research and Development Program of Guangdong Province (2019B110233003, China), the Special Funds for Economic Development of Marine Economy of Guangdong Province (GDME-2018C003, China) and partially by the Grants (SKLRD-OP-201919 and SKLRD-Z-202016) from the State Key Laboratory of Respiratory Disease, Guangzhou Institute of Respiratory Diseases, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
Corresponding author: Tianyu Zhang     Email:zhang_tianyu@gibh.ac.cn
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Yamin Gao
H. M. Adnan Hameed
Yang Liu
Lingmin Guo
Cuiting Fang
Xirong Tian
Zhiyong Liu
Shuai Wang
Zhili Lu
Md Mahmudul Islam
Tianyu Zhang

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