Alpibectir–Ethionamide combination (AlpE) for the treatment of tuberculosis
Abstract
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.
Article Details
Authors (38)
Zainab Edoo
Camille Grosse
Thomas Maitre
Rosangela Frita
Aurélie Chauffour
Sorbonne Université, Paris
Laure Fournier Le Ray
Alexandre Godmer
Alexandra Aubry
Sorbonne Université, Paris
Marilyne Bourotte
Rudy Antoine
Lina Tawk
Stéphanie Slupek
Vincent Trebosc
Birgit Schellhorn
Aurore Dreneau
Line Hofmann
Christian Kemmer
Sergio Lociuro
Glenn E. Dale
BioVersys, Basel, Switzerland
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
BioVersys, Basel, Switzerland
Benoit Deprez
Nicolas Veziris
Sorbonne Université, Paris
Modesto J. Remuiñán
GSK Global Health, Madrid
Nicolas Willand
Michel Pieren
Alain R. Baulard