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 Gao; H M Adnan Hameed; Yang Liu; Lingmin Guo; Cuiting Fang; Xirong Tian; Zhiyong Liu; Shuai Wang; Zhili Lu; Md Mahmudul Islam; Tianyu Zhang

doi:10.1016/j.apsb.2020.11.007

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

Acta Pharm Sin B. 2021 Mar;11(3):738-749. doi: 10.1016/j.apsb.2020.11.007. Epub 2020 Nov 13.

Authors

Yamin Gao^{1

2

3}, H M Adnan Hameed^{1

2

3}, Yang Liu^{1

4}, Lingmin Guo^{1

2

3}, Cuiting Fang^{1

2

3}, Xirong Tian^{1

4}, Zhiyong Liu^{1

3}, Shuai Wang^{1

2

3}, Zhili Lu^{1

3}, Md Mahmudul Islam^{1

2

3}, Tianyu Zhang^{1

2

3}

Affiliations

¹ State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.
² University of Chinese Academy of Sciences, Beijing 100049, China.
³ Guangdong-Hong Kong-Macao Joint Laboratory of Respiratory Infectious Diseases, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.
⁴ Institute of Physical Science and Information Technology, Anhui University, Hefei 230601, China.

Abstract

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.

Keywords: Buruli ulcer; Chemotherapy; Clofazimine; Drug resistance; Electron transport chain; Mycobacterium ulcerans; QcrB; TB47.