Alpibectir–Ethionamide combination (AlpE) for the treatment of tuberculosis
- 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
2026-04-07
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.