Alpibectir–Ethionamide combination (AlpE) for the treatment of tuberculosis
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.
Authors
- Véronique Mégalizzi (ORCID: https://orcid.org/0000-0003-4229-5022)
- David Barros-Aguirre (ORCID: https://orcid.org/0000-0002-4099-0438)
- Vanessa Mathys (ORCID: https://orcid.org/0000-0001-5218-927X)
- Karine Soetaert (ORCID: https://orcid.org/0000-0002-4431-308X)
- Modesto J. Remuiñán (ORCID: https://orcid.org/0000-0001-5574-892X)
- Zainab Edoo (ORCID: https://orcid.org/0000-0001-9003-6370)
- René Wintjens (ORCID: https://orcid.org/0000-0002-0234-7847)
- Marc Gitzinger (ORCID: https://orcid.org/0000-0001-7012-4058)
- Marilyne Bourotte (ORCID: https://orcid.org/0000-0002-4255-7478)
- Line Hofmann
- Lluís Ballell (ORCID: https://orcid.org/0000-0002-3029-1860)
- Thilo Werner (ORCID: https://orcid.org/0000-0003-0688-5834)
- Birgit Schellhorn
- Laure Fournier Le Ray
- Christian Kemmer (ORCID: https://orcid.org/0000-0002-1012-5128)
- Alain R. Baulard (ORCID: https://orcid.org/0000-0002-0150-5241)
- Rudy Antoine (ORCID: https://orcid.org/0000-0002-7369-0626)
- Stéphanie Slupek
- Thomas Maitre (ORCID: https://orcid.org/0000-0002-5463-336X)
- Aurore Dreneau (ORCID: https://orcid.org/0000-0002-8794-8173)
- Sergio Lociuro (ORCID: https://orcid.org/0000-0002-9747-3351)
- Camille Grosse (ORCID: https://orcid.org/0000-0002-9550-4943)
- Nicolas Willand (ORCID: https://orcid.org/0000-0002-0784-0462)
- Michel Pieren (ORCID: https://orcid.org/0000-0001-7896-254X)
- Benoit P. Deprez (ORCID: https://orcid.org/0000-0002-2777-4538)
- Rosangela Frita (ORCID: https://orcid.org/0000-0001-9224-3197)
- Glenn E. Dale
- Alexandre Godmer (ORCID: https://orcid.org/0000-0002-5211-5796)
- Alexandra Aubry (ORCID: https://orcid.org/0000-0003-4230-4793)
- Vincent Trebosc (ORCID: https://orcid.org/0000-0002-8961-1371)
- Lina Tawk
- Aurélie Chauffour
- Alfonso Mendoza
- Maria Jose Rebollo López
- Sonja Ghidelli-Disse
- Esther Pérez-Herrán
- Nicolas Veziris
Institutions
- Centre National de la Recherche Scientifique (FR)
- Université Libre de Bruxelles (BE)
- Inserm (FR)
- Université de Lille (FR)
- Institut Pasteur de Lille (FR)
- Centre Hospitalier Universitaire de Lille (FR)
- Sorbonne Université (FR)
- Assistance Publique – Hôpitaux de Paris (FR)
- Center for Infection and Immunity of Lille (FR)
- Laboratoire National de Référence (MA)
- Heidelberg Engineering (Germany) (DE)
- Centre d'Immunologie et des Maladies Infectieuses (FR)
- Biognosys (Switzerland) (CH)
- Sciensano (Belgium) (BE)
- Living Systems (United States) (US)
- Hôpital Tenon (FR)
- Médicaments et Molécules pour Agir sur les Systèmes Vivants
- GMV Innovating Solutions (Spain) (ES)
Publication Details
- Journal
- Nature Communications
- Published
- 2026-04-07
- DOI
- https://doi.org/10.1038/s41467-026-71460-6
- Primary Topic
- Tuberculosis Research and Epidemiology
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Agence Nationale de la Recherche
- Région Hauts-de-France
- Innovative Medicines Initiative