The small-molecule SMARt751 reverses Mycobacterium tuberculosis resistance to ethionamide in acute and chronic mouse models of tuberculosis.

Autor:	Flipo M; Univ. Lille, Inserm, Institut Pasteur de Lille, U1177 - Drugs and Molecules for living Systems, F-59000 Lille, France., Frita R; Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019 - UMR9017 - CIIL - Center for Infection and Immunity of Lille, F-59000 Lille, France., Bourotte M; Univ. Lille, Inserm, Institut Pasteur de Lille, U1177 - Drugs and Molecules for living Systems, F-59000 Lille, France.; BioVersys SAS, Lille, France., Martínez-Martínez MS; GSK, Tres Cantos R&D, PTM, Tres Cantos, 28760 Madrid, Spain., Boesche M; Cellzome GmbH . A GSK Company, 69117 Heidelberg, Germany., Boyle GW; GSK, David Jack Centre for R&D, Park Road, Ware, Hertfordshire SG12 ODP, UK., Derimanov G; GSK, Clinical Pharmacology and Experimental Medicine, 1250 South Collegeville Road, Collegeville, PA 19426, USA., Drewes G; Cellzome GmbH . A GSK Company, 69117 Heidelberg, Germany., Gamallo P; GSK, Tres Cantos R&D, PTM, Tres Cantos, 28760 Madrid, Spain., Ghidelli-Disse S; Cellzome GmbH . A GSK Company, 69117 Heidelberg, Germany., Gresham S; GSK, David Jack Centre for R&D, Park Road, Ware, Hertfordshire SG12 ODP, UK., Jiménez E; GSK, Tres Cantos R&D, PTM, Tres Cantos, 28760 Madrid, Spain., de Mercado J; GSK, Tres Cantos R&D, PTM, Tres Cantos, 28760 Madrid, Spain., Pérez-Herrán E; GSK, Tres Cantos R&D, PTM, Tres Cantos, 28760 Madrid, Spain., Porras-De Francisco E; GSK, Tres Cantos R&D, PTM, Tres Cantos, 28760 Madrid, Spain., Rullas J; GSK, Tres Cantos R&D, PTM, Tres Cantos, 28760 Madrid, Spain., Casado P; GSK, Tres Cantos R&D, PTM, Tres Cantos, 28760 Madrid, Spain., Leroux F; Univ. Lille, Inserm, Institut Pasteur de Lille, U1177 - Drugs and Molecules for living Systems, F-59000 Lille, France.; Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, US 41 - UAR 2014 - PLBS, F-59000 Lille, France., Piveteau C; Univ. Lille, Inserm, Institut Pasteur de Lille, U1177 - Drugs and Molecules for living Systems, F-59000 Lille, France., Kiass M; National Reference Center for Tuberculosis and Mycobacteria, Sciensano, Brussels, Belgium., Mathys V; National Reference Center for Tuberculosis and Mycobacteria, Sciensano, Brussels, Belgium., Soetaert K; National Reference Center for Tuberculosis and Mycobacteria, Sciensano, Brussels, Belgium., Megalizzi V; Microbiology, Bioorganic and Macromolecular Chemistry, Facult. de Pharmacie, Universit. Libre de Bruxelles, Brussels, Belgium., Tanina A; Microbiology, Bioorganic and Macromolecular Chemistry, Facult. de Pharmacie, Universit. Libre de Bruxelles, Brussels, Belgium., Wintjens R; Microbiology, Bioorganic and Macromolecular Chemistry, Facult. de Pharmacie, Universit. Libre de Bruxelles, Brussels, Belgium., Antoine R; Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019 - UMR9017 - CIIL - Center for Infection and Immunity of Lille, F-59000 Lille, France., Brodin P; Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019 - UMR9017 - CIIL - Center for Infection and Immunity of Lille, F-59000 Lille, France.; Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, US 41 - UAR 2014 - PLBS, F-59000 Lille, France., Delorme V; Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019 - UMR9017 - CIIL - Center for Infection and Immunity of Lille, F-59000 Lille, France., Moune M; Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019 - UMR9017 - CIIL - Center for Infection and Immunity of Lille, F-59000 Lille, France., Djaout K; Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019 - UMR9017 - CIIL - Center for Infection and Immunity of Lille, F-59000 Lille, France., Slupek S; Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019 - UMR9017 - CIIL - Center for Infection and Immunity of Lille, F-59000 Lille, France., Kemmer C; BioVersys AG, Basel, Switzerland., Gitzinger M; BioVersys AG, Basel, Switzerland., Ballell L; GSK, Tres Cantos R&D, PTM, Tres Cantos, 28760 Madrid, Spain., Mendoza-Losana A; GSK, Tres Cantos R&D, PTM, Tres Cantos, 28760 Madrid, Spain., Lociuro S; BioVersys AG, Basel, Switzerland., Deprez B; Univ. Lille, Inserm, Institut Pasteur de Lille, U1177 - Drugs and Molecules for living Systems, F-59000 Lille, France.; Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, US 41 - UAR 2014 - PLBS, F-59000 Lille, France., Barros-Aguirre D; GSK, Tres Cantos R&D, PTM, Tres Cantos, 28760 Madrid, Spain., Remuiñán MJ; GSK, Tres Cantos R&D, PTM, Tres Cantos, 28760 Madrid, Spain., Willand N; Univ. Lille, Inserm, Institut Pasteur de Lille, U1177 - Drugs and Molecules for living Systems, F-59000 Lille, France., Baulard AR; Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019 - UMR9017 - CIIL - Center for Infection and Immunity of Lille, F-59000 Lille, France.; Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, US 41 - UAR 2014 - PLBS, F-59000 Lille, France.
Jazyk:	angličtina
Zdroj:	Science translational medicine [Sci Transl Med] 2022 May 04; Vol. 14 (643), pp. eaaz6280. Date of Electronic Publication: 2022 May 04.
DOI:	10.1126/scitranslmed.aaz6280
Abstrakt:	The sensitivity of Mycobacterium tuberculosis , the pathogen that causes tuberculosis (TB), to antibiotic prodrugs is dependent on the efficacy of the activation process that transforms the prodrugs into their active antibacterial moieties. Various oxidases of M. tuberculosis have the potential to activate the prodrug ethionamide. Here, we used medicinal chemistry coupled with a phenotypic assay to select the N-acylated 4-phenylpiperidine compound series. The lead compound, SMARt751, interacted with the transcriptional regulator VirS of M. tuberculosis , which regulates the mymA operon encoding a monooxygenase that activates ethionamide. SMARt751 boosted the efficacy of ethionamide in vitro and in mouse models of acute and chronic TB. SMARt751 also restored full efficacy of ethionamide in mice infected with M. tuberculosis strains carrying mutations in the ethA gene, which cause ethionamide resistance in the clinic. SMARt751 was shown to be safe in tests conducted in vitro and in vivo. A model extrapolating animal pharmacokinetic and pharmacodynamic parameters to humans predicted that as little as 25 mg of SMARt751 daily would allow a fourfold reduction in the dose of ethionamide administered while retaining the same efficacy and reducing side effects.
Databáze:	MEDLINE
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