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

doi:10.1021/acsinfecdis.9b00277

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 journal › Article › peer-review

16 Citations (Scopus)

Abstract

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 language	English
Pages (from-to)	366-378
Number of pages	13
Journal	ACS Infectious Diseases
Volume	6
Issue number	3
DOIs	https://doi.org/10.1021/acsinfecdis.9b00277
Publication status	Published - 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:
Copyright 2020 Elsevier B.V., All rights reserved.

Keywords

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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10.1021/acsinfecdis.9b00277

Cite this

Villemagne, B., Machelart, A., Tran, N. C., Flipo, M., Moune, M., Leroux, F., Piveteau, C., Wohlkönig, A., Wintjens, R., Li, X., Gref, R., Brodin, P., Deprez, B., Baulard, A. R., & Willand, N. (2020). Fragment-Based Optimized EthR Inhibitors with in Vivo Ethionamide Boosting Activity. ACS Infectious Diseases, 6(3), 366-378. https://doi.org/10.1021/acsinfecdis.9b00277

Villemagne, Baptiste ; Machelart, Arnaud ; Tran, Ngoc Chau ; Flipo, Marion ; Moune, Martin ; Leroux, Florence ; Piveteau, Catherine ; Wohlkönig, Alexandre ; Wintjens, René ; Li, Xue ; Gref, Ruxandra ; Brodin, Priscille ; Deprez, Benoit ; Baulard, Alain R ; Willand, Nicolas. / Fragment-Based Optimized EthR Inhibitors with in Vivo Ethionamide Boosting Activity. In: ACS Infectious Diseases. 2020 ; Vol. 6, No. 3. pp. 366-378.

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abstract = "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.",

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author = "Baptiste Villemagne and Arnaud Machelart and Tran, {Ngoc Chau} and Marion Flipo and Martin Moune and Florence Leroux and Catherine Piveteau and Alexandre Wohlk{\"o}nig and Ren{\'e} Wintjens and Xue Li and Ruxandra Gref and Priscille Brodin and Benoit Deprez and Baulard, {Alain R} and Nicolas Willand",

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, R{\'e}gion Nord-Pas de Calais, FEDER (No 09220019 and 09220020 PRESAGE 31510), ANR (ANR-06-EMPB-033), PRIM: P{\^o}le de Recherche Interdisciplinaire du M{\'e}dicament 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: {\textcopyright} 2020 American Chemical Society. Copyright: Copyright 2020 Elsevier B.V., All rights reserved.",

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doi = "10.1021/acsinfecdis.9b00277",

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Fragment-Based Optimized EthR Inhibitors with in Vivo Ethionamide Boosting Activity. / Villemagne, Baptiste; Machelart, Arnaud; Tran, Ngoc Chau; Flipo, Marion; Moune, Martin; Leroux, Florence; Piveteau, Catherine; Wohlkönig, Alexandre; Wintjens, René; Li, Xue; Gref, Ruxandra; Brodin, Priscille; Deprez, Benoit; Baulard, Alain R; Willand, Nicolas.

In: ACS Infectious Diseases, Vol. 6, No. 3, 13.03.2020, p. 366-378.

Research output: Contribution to journal › Article › peer-review

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AU - Machelart, Arnaud

AU - Tran, Ngoc Chau

AU - Flipo, Marion

AU - Moune, Martin

AU - Leroux, Florence

AU - Piveteau, Catherine

AU - Wohlkönig, Alexandre

AU - Wintjens, René

AU - Li, Xue

AU - Gref, Ruxandra

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PY - 2020/3/13

Y1 - 2020/3/13

N2 - 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.

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KW - Animals

KW - Antitubercular Agents/chemistry

KW - Crystallography, X-Ray

KW - Drug Design

KW - Drug Discovery

KW - Ethionamide/chemistry

KW - Female

KW - Mice

KW - Mice, Inbred BALB C

KW - Mycobacterium tuberculosis/drug effects

KW - Oxadiazoles/chemistry

KW - Repressor Proteins/antagonists & inhibitors

KW - Structure-Activity Relationship

KW - Tuberculosis/drug therapy

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JO - ACS Infectious Diseases

JF - ACS Infectious Diseases

SN - 2373-8227

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ER -

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

Abstract

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Keywords

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