Molecular mechanisms of resistance and treatment efficacy of clofazimine and bedaquiline against Mycobacterium tuberculosis

Md Mahmudul Islam; Md Shah Alam; Zhiyong Liu; Mst Sumaia Khatun; Buhari Yusuf; H M Adnan Hameed; Xirong Tian; Chiranjibi Chhotaray; Rajesh Basnet; Haftay Abraha; Xiaofan Zhang; Shahzad Akbar Khan; Cuiting Fang; Chunyu Li; Sohel Hasan; Shouyong Tan; Nanshan Zhong; Jinxing Hu; Tianyu Zhang

doi:10.3389/fmed.2023.1304857

Molecular mechanisms of resistance and treatment efficacy of clofazimine and bedaquiline against Mycobacterium tuberculosis

Front Med (Lausanne). 2024 Jan 10:10:1304857. doi: 10.3389/fmed.2023.1304857. eCollection 2023.

Authors

Md Mahmudul Islam^{1

2

3

4

5}, Md Shah Alam^{1

2

3

4}, Zhiyong Liu^{1

2

4

6

7}, Mst Sumaia Khatun^{1

2

3

4}, Buhari Yusuf^{1

2

3

4}, H M Adnan Hameed^{1

2

3

4}, Xirong Tian^{1

2

3

4}, Chiranjibi Chhotaray⁸, Rajesh Basnet^{1

2

3

4}, Haftay Abraha^{1

2

3

4}, Xiaofan Zhang^{1

2

3

4}, Shahzad Akbar Khan^{1

2

3

4

9}, Cuiting Fang^{1

2

3

4}, Chunyu Li^{1

2

3

4}, Sohel Hasan¹⁰, Shouyong Tan^{7

11}, Nanshan Zhong^{2

7

12}, Jinxing Hu^{7

11}, Tianyu Zhang^{1

2

3

4}

Affiliations

¹ State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.
² Guangdong-Hong Kong-Macao Joint Laboratory of Respiratory Infectious Diseases, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.
³ University of Chinese Academy of Sciences, Beijing, China.
⁴ China-New Zealand Joint Laboratory on Biomedicine and Health, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.
⁵ Department of Microbiology, Shaheed Shamsuzzoha Institute of Biosciences, Affiliated with University of Rajshahi, Rajshahi, Bangladesh.
⁶ Guangzhou Medical University, Guangzhou, China.
⁷ Guangzhou National Laboratory, Guangzhou, China.
⁸ Department of Medicine, Center for Emerging Pathogens, Rutgers-New Jersey Medical School, Newark, NJ, United States.
⁹ Laboratory of Pathology, Department of Pathobiology, University of Poonch Rawalakot, Azad Kashmir, Pakistan.
¹⁰ Department of Biochemistry and Molecular Biology, University of Rajshahi, Rajshahi, Bangladesh.
¹¹ State Key Laboratory of Respiratory Disease, Guangzhou Chest Hospital, Guangzhou, China.
¹² State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, The National Center for Respiratory Medicine, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.

Abstract

Clofazimine (CFZ) and bedaquiline (BDQ) are currently used for the treatment of multidrug-resistant (MDR) Mycobacterium tuberculosis (Mtb) strains. In recent years, adding CFZ and BDQ to tuberculosis (TB) drug regimens against MDR Mtb strains has significantly improved treatment results, but these improvements are threatened by the emergence of MDR and extensively drug-resistant (XDR) Mtb strains. Recently, CFZ and BDQ have attracted much attention for their strong clinical efficacy, although very little is known about the mechanisms of action, drug susceptibility test (DST), resistance mechanisms, cross-resistance, and pharmacokinetics of these two drugs. In this current review, we provide recent updates on the mechanisms of action, DST, associated mutations with individual resistance and cross-resistance, clinical efficacy, and pharmacokinetics of CFZ and BDQ against Mtb strains. Presently, known mechanisms of resistance for CFZ and/or BDQ include mutations within the Rv0678, pepQ, Rv1979c, and atpE genes. The cross-resistance between CFZ and BDQ may reduce available MDR-/XDR-TB treatment options. The use of CFZ and BDQ for treatment in the setting of limited DST could allow further spread of drug resistance. The DST and resistance knowledge are urgently needed where CFZ and BDQ resistance do emerge. Therefore, an in-depth understanding of clinical efficacy, DST, cross-resistance, and pharmacokinetics for CFZ and BDQ against Mtb can provide new ideas for improving treatment outcomes, reducing mortality, preventing drug resistance, and TB transmission. Along with this, it will also help to develop rapid molecular diagnostic tools as well as novel therapeutic drugs for TB.

Keywords: cross-resistance; drug resistance; mechanism of action; molecular diagnostic; regimens; treatment.

Publication types

Review

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was funded by the National Key R&D Program of China (grant 2021YFA1300900), by the National Natural Science Foundation of China (21920102003), by the Guangzhou Science and Technology Planning Project (2023A03J0992), by the Key R&D Program of Sichuan Provenience (2023YFSY0047) and the State Key Lab of Respiratory Disease, Guangzhou Institute of Respiratory Diseases, First Affiliated Hospital of Guangzhou Medical University (grants SKLRD-OP-202113 and SKLRD-OP-202113).