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Antimycobacterial activity of UDP-galactopyranose mutase inhibitors

Silvia Borrelli1, Wesley F Zandberg, Sankar Mohan

  • 1Department of Chemistry, Simon Fraser University, Burnaby, BC, Canada V5A 1S6.

International Journal of Antimicrobial Agents
|August 4, 2010
PubMed

Insights

A novel pyrazole compound effectively inhibits UDP-galactopyranose mutase (UGM), a key enzyme in mycobacterial cell wall synthesis. This discovery offers a promising new avenue for developing antimycobacterial therapies targeting this essential enzyme.

Area of Science:

  • Microbiology
  • Medicinal Chemistry
  • Drug Discovery

Background:

  • The mycobacterial cell wall contains a unique galactofuran region essential for survival.
  • UDP-galactofuranose (UDP-Galf) is synthesized by UDP-galactopyranose mutase (UGM), an enzyme absent in humans, making it a potential therapeutic target.
  • Targeting UGM offers a selective approach for antimycobacterial drug development.

Purpose of the Study:

  • To evaluate the in vitro properties of two novel compounds, a pyrazole and an aminothiazole, as potential inhibitors of UGM.
  • To assess their antimycobacterial activity, cellular toxicity, and efficacy against mycobacteria in infected macrophages and persistent forms.

Main Methods:

  • Enzymatic assays were performed to determine UGM inhibition.
  • Antimycobacterial activity was tested against various strains, including Mycobacterium tuberculosis, Mycobacterium smegmatis, and Mycobacterium bovis BCG.
  • Cellular toxicity and activity in infected macrophages and against non-replicating persistent mycobacteria were evaluated.

Main Results:

  • The pyrazole compound demonstrated UGM inhibition and broad antimycobacterial activity against M. smegmatis, M. bovis BCG, and M. tuberculosis.
  • This pyrazole compound was effective in infected macrophages but showed moderate cellular toxicity and no activity against non-replicating persistent mycobacteria.
  • The aminothiazole compound showed UGM activity but had higher cellular toxicity and limited antimycobacterial efficacy.

Conclusions:

  • The study validates UGM as a viable therapeutic target for antimycobacterial drug development.
  • The pyrazole compound represents a promising lead candidate for further investigation due to its UGM inhibitory properties and antimycobacterial activity.

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