Reversion of antibiotic resistance in Mycobacterium tuberculosis by spiroisoxazoline SMARt-420

Nicolas Blondiaux (1) , Martin Moune (1) , Matthieu Desroses (2, 3) , Rosangela Frita (1) , Marion Flipo (2) , Vanessa Mathys (4) , Karine Soetaert (4) , Mehdi Kiass (4) , Vincent Delorme (1, 5) , Kamel Djaout (1) , Vincent Trebosc (6, 7) , Christian Kemmer (6) , René Wintjens (8) , Alexandre Wohlkönig (9, 10) , Rudy Antoine (1) , Ludovic Huot (1) , David Hot (1) , Mireia Coscolla (11, 7) , Julia Feldmann (11, 7) , Sebastien Gagneux (11, 7) , Camille Locht (1) , Priscille Brodin (1) , Marc Gitzinger (6) , Benoit Déprez (2) , Nicolas Willand (2) , Alain Baulard (1)

1 CIIL - Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204
2 M2SV - Médicaments et molécules pour agir sur les Systèmes Vivants - U 1177
3 Karolinska Institutet [Stockholm]
4 WIV-ISP - Institut Scientifique de Santé Publique [Belgique] - Scientific Institute of Public Health [Belgium]
5 Tuberculosis Lab [Korea]
6 Bioversys AG [Basel]
7 Unibas - Université de Bâle = University of Basel = Basel Universität
8 ULB - Université libre de Bruxelles
9 VIB-VUB Center for Structural Biology [Bruxelles]
10 VUB - Vrije Universiteit Brussel [Bruxelles]
11 Swiss Tropical and Public Health Institute [Basel]

Antibiotic resistance is one of the biggest threats to human health globally. Alarmingly, multidrug-resistant and extensively drug-resistant Mycobacterium tuberculosis have now spread worldwide. Some key antituberculosis antibiotics are prodrugs, for which resistance mechanisms are mainly driven by mutations in the bacterial enzymatic pathway required for their bioactivation. We have developed drug-like molecules that activate a cryptic alternative bioactivation pathway of ethionamide in M. tuberculosis, circumventing the classic activation pathway in which resistance mutations have now been observed. The first-of-its-kind molecule, named SMARt-420 (Small Molecule Aborting Resistance), not only fully reverses ethionamide-acquired resistance and clears ethionamide-resistant infection in mice, it also increases the basal sensitivity of bacteria to ethionamide.

Domaines: Chimie; Chimie thérapeutique

Nicolas Blondiaux, Martin Moune, Matthieu Desroses, Rosangela Frita, Marion Flipo, et al.. Reversion of antibiotic resistance in Mycobacterium tuberculosis by spiroisoxazoline SMARt-420. Science, 2017, 355 (6330), pp.1206-1211. ⟨10.1126/science.aag1006⟩. ⟨hal-03102877⟩