The small-molecule SMARt751 reverses Mycobacterium tuberculosis resistance to ethionamide in acute and chronic mouse models of tuberculosis - Archive ouverte HAL
Article Dans Une Revue Science Translational Medicine Année : 2022

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

María Martínez-Martínez
Markus Boesche
Gary Boyle
Geo Derimanov
  • Fonction : Auteur
Gerard Drewes
Pablo Gamallo
Sonja Ghidelli-Disse
Stephanie Gresham
Elena Jiménez
Jaime de Mercado
Esther Pérez-Herrán
Esther Porras-de Francisco
Joaquín Rullas
  • Fonction : Auteur
Patricia Casado
Véronique Megalizzi
Abdalkarim Tanina
René Wintjens
Christian Kemmer
Marc Gitzinger
Lluis Ballell
  • Fonction : Auteur
Sergio Lociuro
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David Barros-Aguirre
Modesto Remuiñán
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Résumé

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.
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Dates et versions

hal-04465505 , version 1 (01-05-2024)

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Citer

Marion Flipo, Rosangela Frita, Marilyne Bourotte, María Martínez-Martínez, Markus Boesche, et al.. The small-molecule SMARt751 reverses Mycobacterium tuberculosis resistance to ethionamide in acute and chronic mouse models of tuberculosis. Science Translational Medicine, 2022, 14 (643), ⟨10.1126/scitranslmed.aaz6280⟩. ⟨hal-04465505⟩
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