par Edoo, Zainab;Grosse, Camille 
;Maitre, Thomas;Frita, Rosangela;Chauffour, Aurélie;Fournier Le Ray, Laure;Godmer, Alexandre;Aubry, Alexandra;Bourotte, Marilyne;Antoine, Rudy;Tawk, Lina;Slupek, Stéphanie;Trebosc, Vincent;Schellhorn, Birgit;Dreneau, Aurore;Hofmann, Line;Kemmer, Christian;Lociuro, Sergio;Dale, Glenn G.E.;Jung, Françoise;Pérez-Herrán, Esther;Mendoza, Alfonso;Rebollo López, Maria Jose;Ghidelli-Disse, Sonja;Werner, Thilo;Ballell, Lluis;Barros-Aguirre, David;Mathys, Vanessa ;Soetaert, Karine;Megalizzi, Véronique ;Wintjens, René ;Gitzinger, Marc;Déprez, Benoit;Veziris, Nicolas;Remuiñán, Modesto J.;Willand, Nicolas;Pieren, Michel;Baulard, Alain R
Référence Nature communications, 17, 1
Publication Publié, 2026-04
;Maitre, Thomas;Frita, Rosangela;Chauffour, Aurélie;Fournier Le Ray, Laure;Godmer, Alexandre;Aubry, Alexandra;Bourotte, Marilyne;Antoine, Rudy;Tawk, Lina;Slupek, Stéphanie;Trebosc, Vincent;Schellhorn, Birgit;Dreneau, Aurore;Hofmann, Line;Kemmer, Christian;Lociuro, Sergio;Dale, Glenn G.E.;Jung, Françoise;Pérez-Herrán, Esther;Mendoza, Alfonso;Rebollo López, Maria Jose;Ghidelli-Disse, Sonja;Werner, Thilo;Ballell, Lluis;Barros-Aguirre, David;Mathys, Vanessa ;Soetaert, Karine;Megalizzi, Véronique ;Wintjens, René ;Gitzinger, Marc;Déprez, Benoit;Veziris, Nicolas;Remuiñán, Modesto J.;Willand, Nicolas;Pieren, Michel;Baulard, Alain RRéférence Nature communications, 17, 1
Publication Publié, 2026-04
Article révisé par les pairs
| Résumé : | 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. |
