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

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


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antitubercular Agents / pharmacokinetics
  • Antitubercular Agents / pharmacology*
  • Electron Transport Complex III / antagonists & inhibitors*
  • Extensively Drug-Resistant Tuberculosis / drug therapy*
  • Female
  • Metabolomics
  • Mice
  • Mice, Inbred BALB C
  • Microbial Sensitivity Tests
  • Mycobacterium tuberculosis / drug effects*
  • Pyridines / pharmacology
  • Tuberculosis, Multidrug-Resistant / drug therapy*


  • Antitubercular Agents
  • Pyridines
  • Electron Transport Complex III