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<p>Ethionamide (Eto) and prothionamide (Pto) are second-line antibiotics used for tuberculosis (TB) treatment. Both are prodrugs whose antibacterial activity depends on bioactivation by oxidases in <i>Mycobacterium tuberculosis</i>, including the Baeyer-Villiger monooxygenase MymA. Through biophysical, genetic, and cellular assays, we show that the clinical candidate alpibectir (Alp, BVL-GSK098) binds the transcriptional regulator VirS, increasing MymA expression and potentiating Eto and Pto activity. Alpibectir also boosts the activity of the corresponding host-derived sulfoxide metabolites. We additionally show that alpibectir exhibits intrinsic antibacterial activity via overexpression of the <i>mymA</i> operon. The alpibectir/Eto (AlpE) combination is rapidly bactericidal in vitro and in mice, lowers the frequency of spontaneous resistance of Eto, and remains active on Eto- and isoniazid-resistant strains, including isolates with <i>inhA</i> promoter mutations. Alpibectir was safe in a Phase 1 human clinical trial. Together with the potentiation data presented here, these findings highlight its potential to optimize TB chemotherapy by reducing Eto/Pto doses, which can minimize dose-related side effects, enhancing adherence.</p>

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Alpibectir–Ethionamide combination (AlpE) for the treatment of tuberculosis

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年4月7日

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  • Zainab Edoo,
  • Camille Grosse,
  • Thomas Maitre,
  • Rosangela Frita,
  • Aurélie Chauffour,
  • Laure Fournier Le Ray,
  • Alexandre Godmer,
  • Alexandra Aubry,
  • Marilyne Bourotte,
  • Rudy Antoine,
  • Lina Tawk,
  • Stéphanie Slupek,
  • Vincent Trebosc,
  • Birgit Schellhorn,
  • Aurore Dreneau,
  • Line Hofmann,
  • Christian Kemmer,
  • Sergio Lociuro,
  • Glenn E. Dale,
  • Françoise Jung,
  • Esther Pérez-Herrán,
  • Alfonso Mendoza,
  • Maria Jose Rebollo López,
  • Sonja Ghidelli-Disse,
  • Thilo Werner,
  • Lluis Ballell,
  • David Barros-Aguirre,
  • Vanessa Mathys,
  • Karine Soetaert,
  • Véronique Megalizzi,
  • René Wintjens,
  • Marc Gitzinger,
  • Benoit Deprez,
  • Nicolas Veziris,
  • Modesto J. Remuiñán,
  • Nicolas Willand,
  • Michel Pieren,
  • Alain R. Baulard

摘要

Ethionamide (Eto) and prothionamide (Pto) are second-line antibiotics used for tuberculosis (TB) treatment. Both are prodrugs whose antibacterial activity depends on bioactivation by oxidases in Mycobacterium tuberculosis, including the Baeyer-Villiger monooxygenase MymA. Through biophysical, genetic, and cellular assays, we show that the clinical candidate alpibectir (Alp, BVL-GSK098) binds the transcriptional regulator VirS, increasing MymA expression and potentiating Eto and Pto activity. Alpibectir also boosts the activity of the corresponding host-derived sulfoxide metabolites. We additionally show that alpibectir exhibits intrinsic antibacterial activity via overexpression of the mymA operon. The alpibectir/Eto (AlpE) combination is rapidly bactericidal in vitro and in mice, lowers the frequency of spontaneous resistance of Eto, and remains active on Eto- and isoniazid-resistant strains, including isolates with inhA promoter mutations. Alpibectir was safe in a Phase 1 human clinical trial. Together with the potentiation data presented here, these findings highlight its potential to optimize TB chemotherapy by reducing Eto/Pto doses, which can minimize dose-related side effects, enhancing adherence.