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Related Concept Videos

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Related Experiment Video

Updated: Jun 23, 2026

A High-throughput Compatible Assay to Evaluate Drug Efficacy against Macrophage Passaged Mycobacterium tuberculosis
10:29

A High-throughput Compatible Assay to Evaluate Drug Efficacy against Macrophage Passaged Mycobacterium tuberculosis

Published on: March 24, 2017

Synthetic EthR inhibitors boost antituberculous activity of ethionamide.

Nicolas Willand1, Bertrand Dirié, Xavier Carette

  • 1Institut National de la Santé et de la Recherche Médicale, Lille, France.

Nature Medicine
|May 5, 2009
PubMed
Summary
This summary is machine-generated.

New EthR inhibitors enhance ethionamide efficacy against tuberculosis. This approach boosts drug activation, potentially improving treatment outcomes and reducing resistance risks for thiocarbamide derivatives.

Related Experiment Videos

Last Updated: Jun 23, 2026

A High-throughput Compatible Assay to Evaluate Drug Efficacy against Macrophage Passaged Mycobacterium tuberculosis
10:29

A High-throughput Compatible Assay to Evaluate Drug Efficacy against Macrophage Passaged Mycobacterium tuberculosis

Published on: March 24, 2017

Area of Science:

  • Microbiology
  • Drug Discovery
  • Structural Biology

Background:

  • Tuberculosis (TB) treatment faces challenges from drug side effects, leading to noncompliance and resistance.
  • Many antituberculosis drugs, like ethionamide, require metabolic activation by mycobacterial enzymes.
  • Ethionamide activation is mediated by EthA, whose production is regulated by the repressor EthR.

Purpose of the Study:

  • To identify and develop novel inhibitors of EthR to enhance the bioactivation of ethionamide.
  • To improve the therapeutic index of thiocarbamide-based antituberculosis drugs.

Main Methods:

  • Structure-based drug design and screening targeting EthR-DNA interaction.
  • Co-crystallization of EthR with identified inhibitors.
  • Synthesis and testing of improved EthR inhibitor analogs.
  • In vitro and in vivo efficacy studies in Mycobacterium tuberculosis-infected models.

Main Results:

  • Identification of drug-like EthR inhibitors that significantly boost ethionamide bioactivation.
  • Structure-guided optimization yielded analogs with over tenfold increased ethionamide potency in vitro.
  • A lead analog, BDM31343, demonstrated efficacy in vivo, allowing reduced ethionamide dosage in infected mice.

Conclusions:

  • Inhibiting EthR is a viable strategy to enhance the therapeutic index of ethionamide and other thiocarbamide derivatives.
  • This approach offers a potential pathway to improve TB treatment effectiveness and overcome drug resistance.
  • Reconsideration of ethionamide and related compounds as first-line TB drugs may be warranted.