The compound TB47 is highly bactericidal against Mycobacterium ulcerans in a Buruli ulcer mouse model

Yang Liu, Yamin Gao, Jianxiong Liu, Yaoju Tan, Zhiyong Liu, Chiranjibi Chhotaray, Huofeng Jiang, Zhili Lu, Gift Chiwala, Shuai Wang, Gaelle Makafe, Md Mahmudul Islam, H. M. Adnan Hameed, Xingshan Cai, Changwei Wang, Xinjie Li, Shouyong Tan and Tianyu Zhang ()
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Yang Liu: Chinese Academy of Sciences (CAS)
Yamin Gao: Chinese Academy of Sciences (CAS)
Jianxiong Liu: Guangzhou Chest Hospital
Yaoju Tan: Guangzhou Chest Hospital
Zhiyong Liu: Chinese Academy of Sciences (CAS)
Chiranjibi Chhotaray: Chinese Academy of Sciences (CAS)
Huofeng Jiang: Chinese Academy of Sciences (CAS)
Zhili Lu: Chinese Academy of Sciences (CAS)
Gift Chiwala: Chinese Academy of Sciences (CAS)
Shuai Wang: Chinese Academy of Sciences (CAS)
Gaelle Makafe: Chinese Academy of Sciences (CAS)
Md Mahmudul Islam: Chinese Academy of Sciences (CAS)
H. M. Adnan Hameed: Chinese Academy of Sciences (CAS)
Xingshan Cai: Guangzhou Chest Hospital
Changwei Wang: Chinese Academy of Sciences (CAS)
Xinjie Li: Guangzhou Chest Hospital
Shouyong Tan: Guangzhou Chest Hospital
Tianyu Zhang: Chinese Academy of Sciences (CAS)

Nature Communications, 2019, vol. 10, issue 1, 1-9

Abstract: Abstract Buruli ulcer (BU) is an emerging infectious disease that causes disfiguring skin ulcers. The causative agent, Mycobacterium ulcerans, secretes toxin called mycolactone that triggers inflammation and immunopathology. Existing treatments are lengthy and consist of drugs developed for tuberculosis. Here, we report that a pyrazolo[1,5-a]pyridine-3-carboxamide, TB47, is highly bactericidal against M. ulcerans both in vitro and in vivo. In the validated mouse model of BU, TB47 alone reduces M. ulcerans burden in mouse footpads by more than 2.5 log10 CFU compared to the standard BU treatment regimen recommended by the WHO. We show that mutations of ubiquinol-cytochrome C reductase cytochrome subunit B confer resistance to TB47 and the dissimilarity of CydABs from different mycobacteria may account for their differences in susceptibility to TB47. TB47 is highly potent against M. ulcerans and possesses desirable pharmacological attributes and low toxicity that warrant further assessment of this agent for treatment of BU.

Date: 2019
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DOI: 10.1038/s41467-019-08464-y

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