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Updated: Sep 29, 2025

System for Efficacy and Cytotoxicity Screening of Inhibitors Targeting Intracellular Mycobacterium tuberculosis
09:57

System for Efficacy and Cytotoxicity Screening of Inhibitors Targeting Intracellular Mycobacterium tuberculosis

Published on: April 5, 2017

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A selective PPM1A inhibitor activates autophagy to restrict the survival of Mycobacterium tuberculosis

Stefania Berton1, Lu Chen2, Yi Chu Liang1

  • 1Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON K1H 8M5, Canada.

Cell Chemical Biology
|March 23, 2022
PubMed

Insights

Researchers developed SMIP-30, a selective inhibitor targeting metal-dependent protein phosphatases (PPMs), specifically PPM1A. This discovery offers a new strategy for host-directed tuberculosis therapy by enhancing immune responses.

Area of Science:

  • Immunology and Microbiology
  • Molecular and Cellular Biology
  • Drug Discovery and Development

Background:

  • Metal-dependent protein phosphatases (PPMs) are crucial in cellular processes like inflammation and immunity.
  • Targeting PPMs for pathogen defense is promising but hindered by challenges in inhibitor development and selectivity.
  • Tuberculosis (TB) remains a significant global health challenge, necessitating novel therapeutic approaches.

Purpose of the Study:

  • To design and identify selective inhibitors for PPMs as a potential host-directed therapy against tuberculosis.
  • To investigate the mechanism by which PPM inhibition affects host immunity and intracellular pathogen survival.

Main Methods:

  • Employed a biomimetic modularization strategy and function-oriented synthesis to create over 500 pseudo-natural products.
  • Screened compounds to discover a potent, selective, and non-cytotoxic inhibitor of PPM1A, named SMIP-30.
  • Utilized genetic ablation (ΔPPM1A) and SMIP-30 treatment to study the effects on autophagy and Mycobacterium tuberculosis survival in macrophages and mouse models.

Main Results:

  • Identified SMIP-30, a highly selective small molecule inhibitor of PPM1A.
  • Inhibition of PPM1A (using SMIP-30 or genetic knockout) activated autophagy via p62-SQSTM1 phosphorylation.
  • Activated autophagy restricted the intracellular survival of Mycobacterium tuberculosis in macrophages and in mouse lungs.

Conclusions:

  • PPM1A is a druggable target for modulating host immunity against tuberculosis.
  • SMIP-30 demonstrates proof of concept for PPMs as promising targets for host-directed anti-TB therapies.
  • This study opens avenues for developing novel therapeutic strategies against infectious diseases by targeting host phosphatases.
Keywords:
Mycobacterium tuberculosisPPM1Aautophagyhost-directed therapiesmacrophagesp62-SQSTM1phosphatasessmall molecule PPM inhibitorsxenophagy

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