Identification of pyrvinium pamoate as an anti-tuberculosis agent in vitro and in vivo by SOSA approach amongst known drugs

Emerg Microbes Infect. 2020 Feb 4;9(1):302-312. doi: 10.1080/22221751.2020.1720527. eCollection 2020.

Abstract

Tuberculosis (TB), caused by Mycobacterium tuberculosis (M.tb) bacteria, is a leading infectious cause of mortality worldwide. The emergence of drug-resistant M. tb has made control of TB more difficult. The selective optimization of side activities (SOSA) approach uses old drugs for new pharmacological targets. In the present study by using SOSA approach, we have successfully identified pyrvinium pamoate (PP) which is capable of inhibiting the growth of mycobacteria, including M. tb H37Rv, Mycobacterium smegmatis, Bacille Calmette-Guérin (BCG), M. tb H37Ra, and drug-resistant M. tb clinical isolates in vitro from 1280 known drugs library. The MIC99 of PP, the minimum inhibitory concentration that inhibits more than 99% of M. tb H37Rv and the drug-resistant M. tb clinical isolates, ranges from 1.55 to 4.8 µg/mL. Importantly, PP could reduce the bacterial colony-forming units (CFUs) in lung, spleen and liver tissues, and effectively inhibit inflammatory response in M. tb H37Rv, multidrug-resistant (MDR) M. tb and extensively drug-resistant (XDR) M.tb-infected mice. Our results clearly show that the PP has the potential application for treatment of TB.

Keywords: Mycobacterium tuberculosis; anti-TB drug screening; multidrug-resistant M. tb; pyrvinium pamoate; selective optimization of side activities approach.

MeSH terms

  • Animals
  • Antitubercular Agents / pharmacology*
  • Antitubercular Agents / therapeutic use
  • Drug Resistance, Bacterial
  • Mice
  • Mycobacterium tuberculosis / drug effects*
  • Pyrvinium Compounds / pharmacology*
  • Pyrvinium Compounds / therapeutic use
  • Tuberculosis / drug therapy

Substances

  • Antitubercular Agents
  • Pyrvinium Compounds
  • pyrvinium

Grants and funding

This work was supported by grants from the National Key R & D Program of China (2018YFA0507603), National Science and Technology Major Project of China (2017ZX10201301-006, 2012ZX10003002-015), National Natural Science Foundation of China (91740120, 21572173, 31770145 and 81971908), National Outstanding Youth Foundation of China (81025008), the Major Projects of Technological Innovation of Hubei Province (2016ACA150), Natural Science Foundation Project of Hubei Province (2016CFA062), the Outstanding Youth Foundation of Hubei Province (2018CFA037), CAMS Innovation Funding For Medical Sciences (2016-I2M-2-006 and 2016-I2M-1-013), Medical Science Advancement Program (Basical Medical Sciences) of Wuhan University (TFJC 2018002) and the Hubei Province’s Outstanding Medical Academic Leader Program (523-276003).