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ACS Infect Dis. 2019 Feb 8;5(2):239-249. doi: 10.1021/acsinfecdis.8b00225. Epub 2018 Dec 11.

Pyrazolo[1,5- a]pyridine Inhibitor of the Respiratory Cytochrome bcc Complex for the Treatment of Drug-Resistant Tuberculosis.

Author information

1
School of Pharmacy , Jinan University , 601 Huangpu Avenue West , Guangzhou 510632 , China.
2
Department of Microbiology and Immunology, School of Biomedical Sciences , University of Otago , Dunedin 9054 , New Zealand.
3
Maurice Wilkins Centre for Molecular Biodiscovery , The University of Auckland , Private Bag 92019 , Auckland 1042 , New Zealand.
4
Tuberculosis Research Laboratory, State Key Laboratory of Respiratory Disease, Guangzhou Regenerative Medicine and Health Guangdong Laboratory , Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences , 190 Kaiyuan Avenue , Science Park, Huangpu District, Guangzhou 510530 , China.
5
University of Chinese Academy of Sciences (UCAS) , 19 Yuquan Road , Shijingshan District, Beijing 100049 , China.
6
Institute of Physical Science and Information Technology , Anhui University , 111 Jiulong Road , Shushan District, Hefei 230009 , China.
7
Colorado State University , 200W Lake Street , Fort Collins , Colorado 80523 , United States.
8
Guangzhou Eggbio Co., Ltd. , 3 Ju Quan Road , Science Park, Guangzhou 510663 , China.
9
Weill Department of Medicine , Weill Cornell Medical College , New York , New York 10021 , United States.

Abstract

Respiration is a promising target for the development of new antimycobacterial agents, with a growing number of compounds in clinical development entering this target space. However, more candidate inhibitors are needed to expand the therapeutic options available for drug-resistant Mycobacterium tuberculosis infection. Here, we characterize a putative respiratory complex III (QcrB) inhibitor, TB47: a pyrazolo[1,5- a]pyridine-3-carboxamide. TB47 is active (MIC between 0.016 and 0.500 μg/mL) against a panel of 56 M. tuberculosis clinical isolates, including 37 multi-drug-resistant and two extensively drug-resistant strains. Pharmacokinetic and toxicity studies showed promising profiles, including negligible CYP450 interactions, cytotoxicity, and hERG channel inhibition. Consistent with other reported QcrB inhibitors, TB47 inhibits oxygen consumption only when the alternative oxidase, cytochrome bd, is deleted. A point mutation in the qcrB cd2-loop (H190Y, M. smegmatis numbering) rescues the inhibitory effects of TB47. Metabolomic profiling of TB47-treated M. tuberculosis H37Rv cultures revealed accumulation of steps in the TCA cycle and pentose phosphate pathway that are linked to reducing equivalents, suggesting that TB47 causes metabolic redox stress. In mouse infection models, a TB47 monotherapy was not bactericidal. However, TB47 was strongly synergistic with pyrazinamide and rifampicin, suggesting a promising role in combination therapies. We propose that TB47 is an effective lead compound for the development of novel tuberculosis chemotherapies.

KEYWORDS:

Mycobacterium tuberculosis; QcrB; cytochrome bcc complex; respiratory inhibitor; tuberculosis

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