1. The small-molecule SMARt751 reverses Mycobacterium tuberculosis resistance to ethionamide in acute and chronic mouse models of tuberculosis
- Author
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Marion Flipo, Rosangela Frita, Marilyne Bourotte, María S. Martínez-Martínez, Markus Boesche, Gary W. Boyle, Geo Derimanov, Gerard Drewes, Pablo Gamallo, Sonja Ghidelli-Disse, Stephanie Gresham, Elena Jiménez, Jaime de Mercado, Esther Pérez-Herrán, Esther Porras-De Francisco, Joaquín Rullas, Patricia Casado, Florence Leroux, Catherine Piveteau, Mehdi Kiass, Vanessa Mathys, Karine Soetaert, Véronique Megalizzi, Abdalkarim Tanina, René Wintjens, Rudy Antoine, Priscille Brodin, Vincent Delorme, Martin Moune, Kamel Djaout, Stéphanie Slupek, Christian Kemmer, Marc Gitzinger, Lluis Ballell, Alfonso Mendoza-Losana, Sergio Lociuro, Benoit Deprez, David Barros-Aguirre, Modesto J. Remuiñán, Nicolas Willand, and Alain R. Baulard
- Subjects
General Medicine - Abstract
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.
- Published
- 2022
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