title: Reversion of antibiotic resistance inMycobacterium tuberculosisby spiroisoxazoline SMARt-420.
abstract: Antibiotic resistance is one of the biggest threats to human health globally. Alarmingly, multidrug-resistant and extensively drug-resistantMycobacterium tuberculosishave 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 inM. 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.
authors.affiliation: Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019-UMR8204-CIIL-Center for Infection and Immunity of Lille, F-59000 Lille, France.
authors.forename: Nicolas
authors.identifier: 0000-0002-9762-7322
authors.initials: N
authors.lastname: Blondiaux
authors.affiliation: Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019-UMR8204-CIIL-Center for Infection and Immunity of Lille, F-59000 Lille, France.
authors.forename: Martin
authors.identifier: 0000-0003-4780-528X
authors.initials: M
authors.lastname: Moune
authors.affiliation: Université Lille, Inserm, Institut Pasteur de Lille, U1177-Drugs and Molecules for Living Systems, F-59000 Lille, France.|Division of Translational Medicine and Chemical Biology, Science for Life Laboratory, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Matthieu
authors.identifier: 0000-0003-4152-3855
authors.initials: M
authors.lastname: Desroses
authors.affiliation: Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019-UMR8204-CIIL-Center for Infection and Immunity of Lille, F-59000 Lille, France.
authors.forename: Rosangela
authors.identifier: 0000-0001-9224-3197
authors.initials: R
authors.lastname: Frita
authors.affiliation: Université Lille, Inserm, Institut Pasteur de Lille, U1177-Drugs and Molecules for Living Systems, F-59000 Lille, France.
authors.forename: Marion
authors.identifier: 0000-0003-2863-5721
authors.initials: M
authors.lastname: Flipo
authors.affiliation: National Reference Center for Tuberculosis and Mycobacteria, Bacterial Diseases Service, Operational Direction Communicable and Infectious Diseases, Scientific Institute of Public Health (WIV-ISP), Brussels, Belgium.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Mathys
authors.affiliation: National Reference Center for Tuberculosis and Mycobacteria, Bacterial Diseases Service, Operational Direction Communicable and Infectious Diseases, Scientific Institute of Public Health (WIV-ISP), Brussels, Belgium.
authors.forename: Karine
authors.initials: K
authors.lastname: Soetaert
authors.affiliation: National Reference Center for Tuberculosis and Mycobacteria, Bacterial Diseases Service, Operational Direction Communicable and Infectious Diseases, Scientific Institute of Public Health (WIV-ISP), Brussels, Belgium.
authors.forename: Mehdi
authors.initials: M
authors.lastname: Kiass
authors.affiliation: Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019-UMR8204-CIIL-Center for Infection and Immunity of Lille, F-59000 Lille, France.|Tuberculosis Research Laboratory, Institut Pasteur Korea, South Korea.
authors.forename: Vincent
authors.identifier: 0000-0001-5235-7069
authors.initials: V
authors.lastname: Delorme
authors.affiliation: Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019-UMR8204-CIIL-Center for Infection and Immunity of Lille, F-59000 Lille, France.
authors.forename: Kamel
authors.identifier: 0000-0002-5531-9882
authors.initials: K
authors.lastname: Djaout
authors.affiliation: Bioversys AG, Hochbergerstrasse 60C, 4057 Basel, Switzerland.|Biozentrum, University of Basel, Basel, Switzerland.
authors.forename: Vincent
authors.initials: V
authors.lastname: Trebosc
authors.affiliation: Bioversys AG, Hochbergerstrasse 60C, 4057 Basel, Switzerland.
authors.forename: Christian
authors.initials: C
authors.lastname: Kemmer
authors.affiliation: Laboratoire des Biopolymères et des Nanomatériaux Supramoléculaires, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: René
authors.identifier: 0000-0002-0234-7847
authors.initials: R
authors.lastname: Wintjens
authors.affiliation: VIB Center for Structural Biology, VIB, Pleinlaan 2, 1050 Brussels, Belgium.|Structural Biology Brussels, Vrije Universiteit Brussel (VUB), Pleinlaan 2, 1050 Brussels, Belgium.
authors.forename: Alexandre
authors.identifier: 0000-0003-3103-5022
authors.initials: A
authors.lastname: Wohlkönig
authors.affiliation: Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019-UMR8204-CIIL-Center for Infection and Immunity of Lille, F-59000 Lille, France.
authors.forename: Rudy
authors.initials: R
authors.lastname: Antoine
authors.affiliation: Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019-UMR8204-CIIL-Center for Infection and Immunity of Lille, F-59000 Lille, France.
authors.forename: Ludovic
authors.identifier: 0000-0003-0896-4368
authors.initials: L
authors.lastname: Huot
authors.affiliation: Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019-UMR8204-CIIL-Center for Infection and Immunity of Lille, F-59000 Lille, France.
authors.forename: David
authors.initials: D
authors.lastname: Hot
authors.affiliation: Swiss Tropical and Public Health Institute, Basel, Switzerland.|University of Basel, Basel, Switzerland.
authors.forename: Mireia
authors.initials: M
authors.lastname: Coscolla
authors.affiliation: Swiss Tropical and Public Health Institute, Basel, Switzerland.|University of Basel, Basel, Switzerland.
authors.forename: Julia
authors.identifier: 0000-0001-8389-369X
authors.initials: J
authors.lastname: Feldmann
authors.affiliation: Swiss Tropical and Public Health Institute, Basel, Switzerland.|University of Basel, Basel, Switzerland.
authors.forename: Sebastien
authors.initials: S
authors.lastname: Gagneux
authors.affiliation: Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019-UMR8204-CIIL-Center for Infection and Immunity of Lille, F-59000 Lille, France.
authors.forename: Camille
authors.initials: C
authors.lastname: Locht
authors.affiliation: Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019-UMR8204-CIIL-Center for Infection and Immunity of Lille, F-59000 Lille, France.
authors.forename: Priscille
authors.identifier: 0000-0003-0991-7344
authors.initials: P
authors.lastname: Brodin
authors.affiliation: Bioversys AG, Hochbergerstrasse 60C, 4057 Basel, Switzerland.
authors.forename: Marc
authors.identifier: 0000-0001-7012-4058
authors.initials: M
authors.lastname: Gitzinger
authors.affiliation: Université Lille, Inserm, Institut Pasteur de Lille, U1177-Drugs and Molecules for Living Systems, F-59000 Lille, France. benoit.deprez@univ-lille2.fr nicolas.willand@univ-lille2.fr alain.baulard@inserm.fr.
authors.forename: Benoit
authors.identifier: 0000-0002-2777-4538
authors.initials: B
authors.lastname: Déprez
authors.affiliation: Université Lille, Inserm, Institut Pasteur de Lille, U1177-Drugs and Molecules for Living Systems, F-59000 Lille, France. benoit.deprez@univ-lille2.fr nicolas.willand@univ-lille2.fr alain.baulard@inserm.fr.
authors.forename: Nicolas
authors.identifier: 0000-0002-0784-0462
authors.initials: N
authors.lastname: Willand
authors.affiliation: Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019-UMR8204-CIIL-Center for Infection and Immunity of Lille, F-59000 Lille, France. benoit.deprez@univ-lille2.fr nicolas.willand@univ-lille2.fr alain.baulard@inserm.fr.
authors.forename: Alain R
authors.identifier: 0000-0002-0150-5241
authors.initials: AR
authors.lastname: Baulard
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000494:pharmacology*; D004247:DNA / Q000378:metabolism; D024901:Drug Resistance, Multiple, Bacterial / Q000187:drug effects*; D005000:Ethionamide / Q000378:metabolism* / Q000494:pharmacology; D054908:Extensively Drug-Resistant Tuberculosis / Q000382:microbiology*; D006801:Humans; D007555:Isoxazoles / Q000494:pharmacology*; D051379:Mice; D009154:Mutation; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D010069:Oxadiazoles / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D012097:Repressor Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D013141:Spiro Compounds / Q000494:pharmacology*
chemical_list: C570905:5,5,5-trifluoro-1-(4-(3-thiazol-2-yl-1,2,4-oxadiazol-5-yl)piperidin-1-yl)pentan-1-one; D000995:Antitubercular Agents; C481661:EthR protein, Mycobacterium tuberculosis; D007555:Isoxazoles; D010069:Oxadiazoles; D010880:Piperidines; D012097:Repressor Proteins; C000620864:SMARt-420; D013141:Spiro Compounds; D004247:DNA; D005000:Ethionamide