Year: 2026
Type: article
Abstract: 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.
Source: Nature Communications
Authors: 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
Institutions: Centre National de la Recherche Scientifique, Inserm, Université de Lille, Institut Pasteur de Lille, Center for Infection and Immunity of Lille, BioVersys AG (Switzerland), Université Libre de Bruxelles, Sorbonne Université, Assistance Publique – Hôpitaux de Paris, Centre d'Immunologie et des Maladies Infectieuses, Hôpital Tenon, SoLID : SOrbonne study group for Lung Infectious Diseases, Hôpital Saint-Antoine, Pitié-Salpêtrière Hospital, GlaxoSmithKline (Spain), GlaxoSmithKline (Germany), Sciensano (Belgium), Centre Hospitalier Universitaire de Lille, Plateformes Lilloises en Biologie et Santé, Médicaments et Molécules pour Agir sur les Systèmes Vivants
Language: English
Subfield: Infectious Diseases
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $6,990
OpenAlex ID: W7151214022