8RCX

Crystal structure of the Mycobacterium tuberculosis regulator VirS (N-terminal fragment 4-208) in complex with the drug candidate alpibectir

Summary for 8RCX

• Entry DOI: 10.2210/pdb8rcx/pdb
• Descriptor: HTH-type transcriptional regulator VirS, 4,4,4-tris(fluoranyl)-1-[3-(trifluoromethyl)-1-oxa-2,8-diazaspiro[4.5]dec-2-en-8-yl]butan-1-one (3 entities in total)
• Functional Keywords: arac family, transcription, tuberculosis, dna binding protein, in situ proteolysis
• Biological source: Mycobacterium tuberculosis H37Rv
• Total number of polymer chains: 2
• Total formula weight: 89811.04

Authors

Edoo, Z.,Frita, R.,Grosse, C.,Bourotte, M.,Moune, M.,Antoine, R.,Trebosc, V.,Schellhorn, B.,Dreneau, A.,Hofmann, L.,Kemmer, C.,Lociuro, S.,Dale, G.E.,Jung, F.,Perez-Herran, E.,Mendoza, A.,Rebollo Lopez, M.J.,Ghidelli-Disse, S.,Drewes, G.,Mathys, V.,Soetaert, K.,Megalizzi, V.,Wintjens, R.,Barros Aguirre, D.,Remuinan, M.D.,Gitzinger, M.,Deprez, B.,Willand, N.,Pieren, M.,Baulard, A.R. (deposition date: 2023-12-07, release date: 2025-10-29, Last modification date: 2026-05-13)

Primary citation

Edoo, Z.,Grosse, C.,Maitre, T.,Frita, R.,Chauffour, A.,Fournier Le Ray, L.,Godmer, A.,Aubry, A.,Bourotte, M.,Antoine, R.,Tawk, L.,Slupek, S.,Trebosc, V.,Schellhorn, B.,Dreneau, A.,Hofmann, L.,Kemmer, C.,Lociuro, S.,Dale, G.E.,Jung, F.,Perez-Herran, E.,Mendoza, A.,Rebollo Lopez, M.J.,Ghidelli-Disse, S.,Werner, T.,Ballell, L.,Barros-Aguirre, D.,Mathys, V.,Soetaert, K.,Megalizzi, V.,Wintjens, R.,Gitzinger, M.,Deprez, B.,Veziris, N.,Remuinan, M.J.,Willand, N.,Pieren, M.,Baulard, A.R.
Alpibectir-Ethionamide combination (AlpE) for the treatment of tuberculosis.
Nat Commun, 2026

PubMed 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.

PubMed: 41946736
DOI: 10.1038/s41467-026-71460-6

Experimental method

X-RAY DIFFRACTION (1.494 Å)