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Science. 2017 Mar 17;355(6330):1206-1211. doi: 10.1126/science.aag1006. Epub 2017 Mar 16.

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

Author information

1
Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019-UMR8204-CIIL-Center for Infection and Immunity of Lille, F-59000 Lille, France.
2
Université Lille, Inserm, Institut Pasteur de Lille, U1177-Drugs and Molecules for Living Systems, F-59000 Lille, France.
3
Division of Translational Medicine and Chemical Biology, Science for Life Laboratory, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
4
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.
5
Tuberculosis Research Laboratory, Institut Pasteur Korea, South Korea.
6
Bioversys AG, Hochbergerstrasse 60C, 4057 Basel, Switzerland.
7
Biozentrum, University of Basel, Basel, Switzerland.
8
Laboratoire des Biopolymères et des Nanomatériaux Supramoléculaires, Université Libre de Bruxelles, Brussels, Belgium.
9
VIB Center for Structural Biology, VIB, Pleinlaan 2, 1050 Brussels, Belgium.
10
Structural Biology Brussels, Vrije Universiteit Brussel (VUB), Pleinlaan 2, 1050 Brussels, Belgium.
11
Swiss Tropical and Public Health Institute, Basel, Switzerland.
12
University of Basel, Basel, Switzerland.
13
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.
14
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.

Abstract

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.

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PMID:
28302858
DOI:
10.1126/science.aag1006
[Indexed for MEDLINE]

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