Structural analysis of the interaction between spiroisoxazoline SMARt-420 and the Mycobacterium tuberculosis repressor EthR2

Biochem Biophys Res Commun. 2017 May 27;487(2):403-408. doi: 10.1016/j.bbrc.2017.04.074. Epub 2017 Apr 14.


Inhibition of transcriptional regulators of bacterial pathogens with the aim of reprogramming their metabolism to modify their antibiotic susceptibility constitutes a promising therapeutic strategy. One example is the bio-activation of the anti-tubercular pro-drug ethionamide, which activity could be enhanced by inhibiting the transcriptional repressor EthR. Recently, we discovered that inhibition of a second transcriptional repressor, EthR2, leads to the awakening of a new ethionamide bio-activation pathway. The x-ray structure of EthR2 was solved at 2.3 Å resolution in complex with a compound called SMARt-420 (Small Molecule Aborting Resistance). Detailed comparison and structural analysis revealed interesting insights for the upcoming structure-based design of EthR2 inhibitors as an alternative to revert ethionamide resistance in Mycobacterium tuberculosis.

Keywords: Crystal structure; Drug design; Ethionamide; Ligand-binding interaction; TetR family; Transcriptional repressor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antitubercular Agents / chemistry*
  • Bacterial Proteins / chemistry*
  • Bacterial Proteins / ultrastructure*
  • Binding Sites
  • Isoxazoles / chemistry*
  • Models, Chemical
  • Molecular Docking Simulation*
  • Mycobacterium tuberculosis / metabolism*
  • Protein Binding
  • Protein Conformation
  • Protein Interaction Mapping
  • Repressor Proteins / chemistry*
  • Repressor Proteins / ultrastructure*
  • Spiro Compounds / chemistry*
  • Structure-Activity Relationship


  • Antitubercular Agents
  • Bacterial Proteins
  • Isoxazoles
  • Repressor Proteins
  • Spiro Compounds