Fragment-Based Optimized EthR Inhibitors with in Vivo Ethionamide Boosting Activity

Baptiste Villemagne, Arnaud Machelart, Ngoc Chau Tran, Marion Flipo, Martin Moune, Florence Leroux, Catherine Piveteau, Alexandre Wohlkönig, René Wintjens, Xue Li, Ruxandra Gref, Priscille Brodin, Benoit Deprez, Alain R Baulard, Nicolas Willand

Research output: Contribution to journalArticle

8 Citations (Scopus)


Killing more than one million people each year, tuberculosis remains the leading cause of death from a single infectious agent. The growing threat of multidrug-resistant strains of Mycobacterium tuberculosis stresses the need for alternative therapies. EthR, a mycobacterial transcriptional regulator, is involved in the control of the bioactivation of the second-line drug ethionamide. We have previously reported the discovery of in vitro nanomolar boosters of ethionamide through fragment-based approaches. In this study, we have further explored the structure-activity and structure-property relationships in this chemical family. By combining structure-based drug design and in vitro evaluation of the compounds, we identified a new oxadiazole compound as the first fragment-based ethionamide booster which proved to be active in vivo, in an acute model of tuberculosis infection.

Original languageEnglish
Pages (from-to)366-378
Number of pages13
JournalACS Infectious Diseases
Issue number3
Publication statusPublished - 13 Mar 2020


  • Animals
  • Antitubercular Agents/chemistry
  • Crystallography, X-Ray
  • Drug Design
  • Drug Discovery
  • Ethionamide/chemistry
  • Female
  • Mice
  • Mice, Inbred BALB C
  • Mycobacterium tuberculosis/drug effects
  • Oxadiazoles/chemistry
  • Repressor Proteins/antagonists & inhibitors
  • Structure-Activity Relationship
  • Tuberculosis/drug therapy


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