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  2. Discovery and Mechanistic Study of Mycobacterium tuberculosis PafA Inhibitors

Discovery and Mechanistic Study of Mycobacterium tuberculosis PafA Inhibitors

  • J Med Chem. 2022 Aug 25;65(16):11058-11065. doi: 10.1021/acs.jmedchem.2c00289.
Cong Li 1 Song Liu 2 Baoyu Dong 3 Chungen Li 2 Lunan Jian 1 Juan He 2 Jumei Zeng 3 Qiao Zhou 1 Da Jia 4 Youfu Luo 2 Qingxiang Sun 1
Affiliations

Affiliations

  • 1 Department of Pathology, State Key Laboratory of Biotherapy and Cancer Centre, West China Hospital, Sichuan University, and Collaborative Innovation Centre of Biotherapy, Chengdu 610041, P. R. China.
  • 2 State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, P. R. China.
  • 3 West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu 610041, Sichuan, P. R. China.
  • 4 Key Laboratory of Birth Defects and Related Diseases of Women and Children, Department of Pediatrics, Division of Neurology, West China Second University Hospital, Sichuan University, Chengdu 610041, P. R. China.
Abstract

Tuberculosis is caused by the bacterium Mycobacterium tuberculosis (Mtb) and is ranked as the second killer infectious disease after COVID-19. Proteasome accessory factor A (PafA) is considered an attractive target because of its low sequence conservation in humans and its role in virulence. In this study, we designed a mutant of Mtb PafA that enabled large-scale purification of active PafA. Using a devised high-throughput screening assay, two PafA inhibitors were discovered. ST1926 inhibited Mtb PafA by binding in the Pup binding groove, but it was less active against Corynebacterium glutamicum PafA because the ST1926-binding residues are not conserved. Bithionol bound to the conserved ATP-binding pocket, thereby, inhibits PafA in an ATP-competitive manner. Both ST1926 and bithionol inhibited the growth of an attenuated Mtb strain (H37Ra) at micromolar concentrations. Our work thus provides new tools for tuberculosis research and a foundation for future PafA-targeted drug development for treating tuberculosis.

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