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 journalArticlepeer-review

12 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

Bibliographical note

Funding Information:
Baptiste Villemagne was recipient of a doctoral fellowship MENR and Ngoc Chau Tran was the recipient of a AUF doctoral fellowship. We are grateful to the institutions that support our laboratories (Inserm, INSERM-Avenir fellowship to Priscille Brodin, Institut Pasteur Korea (Grants: K204EA000001-08E0100-00100 and K204EA000001-09E0100-00100), Univ Lille Nord de France, Institut Pasteur de Lille, CNRS, EU, Région Nord-Pas de Calais, FEDER (No 09220019 and 09220020 PRESAGE 31510), ANR (ANR-06-EMPB-033), PRIM: Pôle de Recherche Interdisciplinaire du Médicament and the European Commission under the seventh Framework Program: Research Infrastructures (Grant Agreement Number 226716)). Financial support to Arnaud Machelart for this work was provided by Fondation pour la Recherche Medicale (SPF20170938709), the European Community (CycloNHit no 608407) and the Agence Nationale de la Recherche (ANR-10-EQPX-04-01, ANR-14-CE08-0017, ANR-16-CE35-0009). Diffraction data were collected at the Swiss Light Source (Paul Scherrer Institute, Villigen, Switzerland). We are grateful to the machine and beamline scientists whose outstanding efforts have made these experiments possible. Data management was performed using Pipeline Pilot from Accelrys. We thank VARIAN Inc. for their technical support. NMR acquisitions were done by the LARMN, Lille and SPR acquisitions were done at the molecular interaction platform (IMPRT-IFR114).

Publisher Copyright:
© 2020 American Chemical Society.

Copyright 2020 Elsevier B.V., All rights reserved.


  • 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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