Sterilizing Effects of Novel Regimens Containing TB47, Clofazimine, and Linezolid in a Murine Model of Tuberculosis

Wei Yu; Buhari Yusuf; Shuai Wang; Xirong Tian; H M Adnan Hameed; Zhili Lu; Gift Chiwala; Md Shah Alam; Gregory M Cook; Dmitry A Maslov; Nanshan Zhong; Tianyu Zhang

doi:10.1128/AAC.00706-21

Sterilizing Effects of Novel Regimens Containing TB47, Clofazimine, and Linezolid in a Murine Model of Tuberculosis

Antimicrob Agents Chemother. 2021 Sep 17;65(10):e0070621. doi: 10.1128/AAC.00706-21. Epub 2021 Jul 19.

Authors

Wei Yu^#^{1

2

3}, Buhari Yusuf^#^{1

2

3}, Shuai Wang^{1

2

3}, Xirong Tian^{1

2

4}, H M Adnan Hameed^{1

2}, Zhili Lu^{1

2}, Gift Chiwala^{1

2

3}, Md Shah Alam^{1

2

3}, Gregory M Cook^{5

6}, Dmitry A Maslov⁷, Nanshan Zhong^{2

8}, Tianyu Zhang^{1

2

3}

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 Institute of Physical Science and Information Technology, Anhui University, Hefei, China.
⁵ Department of Microbiology and Immunology, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand.
⁶ Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Auckland, New Zealand.
⁷ Laboratory of Bacterial Genetics, Vavilov Institute of General Genetics, Russian Academy of Sciences, Moscow, Russia.
⁸ 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.

^# Contributed equally.

Abstract

TB47, a new drug candidate targeting QcrB in the electron transport chain, has shown a unique synergistic activity with clofazimine and forms a highly sterilizing combination. Here, we investigated the sterilizing effects of several all-oral regimens containing TB47 plus clofazimine and linezolid as a block and the roles of fluoroquinolones and pyrazinamide in them. All these regimens cured tuberculosis within 4 to 6 months in a well-established mouse model, and adding pyrazinamide showed a significant difference in bactericidal effects.

Keywords: TB47; cytochrome bc1-aa3 oxidase; drug resistance; murine model; tuberculosis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antitubercular Agents / therapeutic use
Clofazimine / therapeutic use
Disease Models, Animal
Linezolid
Mice
Mice, Inbred BALB C
Mycobacterium tuberculosis*
Tuberculosis* / drug therapy

Substances

Antitubercular Agents
Clofazimine
Linezolid