reverse resistance

Nicolas Blondiaux; Martin Moune; Matthieu Desroses; Rosangela Frita; Marion Flipo; Vanessa Mathys; Karine Soetaert; Mehdi Kiass; Vincent Delorme; Kamel Djaout; Vincent Trebosc; Christian Kemmer; René Wintjens; Alexandre Wohlkönig; Rudy Antoine; Ludovic Huot; David Hot; Mireia Coscolla; Julia Feldmann; Sebastien Gagneux; Camille Locht; Priscille Brodin; Marc Gitzinger; Benoit Déprez; Nicolas Willand; Alain R. Baulard

doi:10.1126/science.aag1006

reverse resistance

Nicolas Blondiaux, Martin Moune, Matthieu Desroses, Rosangela Frita, Marion Flipo, Vanessa Mathys, Karine Soetaert, Mehdi Kiass, Vincent Delorme, Kamel Djaout, Vincent Trebosc, Christian Kemmer, René Wintjens, Alexandre Wohlkönig, Rudy Antoine, Ludovic Huot, David Hot, Mireia Coscolla, Julia Feldmann, Sebastien GagneuxCamille Locht, Priscille Brodin, Marc Gitzinger, Benoit Déprez, Nicolas Willand, Alain R. Baulard

Research output: Contribution to journal › Article › peer-review

120 Citations (Scopus)

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.

Original language	English
Pages (from-to)	1206-1211
Number of pages	6
Journal	Science
Volume	355
Issue number	6330
DOIs	https://doi.org/10.1126/science.aag1006
Publication status	Published - 2017

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Blondiaux, Nicolas ; Moune, Martin ; Desroses, Matthieu ; Frita, Rosangela ; Flipo, Marion ; Mathys, Vanessa ; Soetaert, Karine ; Kiass, Mehdi ; Delorme, Vincent ; Djaout, Kamel ; Trebosc, Vincent ; Kemmer, Christian ; Wintjens, René ; Wohlkönig, Alexandre ; Antoine, Rudy ; Huot, Ludovic ; Hot, David ; Coscolla, Mireia ; Feldmann, Julia ; Gagneux, Sebastien ; Locht, Camille ; Brodin, Priscille ; Gitzinger, Marc ; Déprez, Benoit ; Willand, Nicolas ; Baulard, Alain R. / reverse resistance. In: Science. 2017 ; Vol. 355, No. 6330. pp. 1206-1211.

@article{d49e3dfc68fb44a3a8594e14b9b81c7f,

title = "reverse resistance",

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.",

author = "Nicolas Blondiaux and Martin Moune and Matthieu Desroses and Rosangela Frita and Marion Flipo and Vanessa Mathys and Karine Soetaert and Mehdi Kiass and Vincent Delorme and Kamel Djaout and Vincent Trebosc and Christian Kemmer and Ren{\'e} Wintjens and Alexandre Wohlk{\"o}nig and Rudy Antoine and Ludovic Huot and David Hot and Mireia Coscolla and Julia Feldmann and Sebastien Gagneux and Camille Locht and Priscille Brodin and Marc Gitzinger and Benoit D{\'e}prez and Nicolas Willand and Baulard, {Alain R.}",

year = "2017",

doi = "10.1126/science.aag1006",

language = "English",

volume = "355",

pages = "1206--1211",

journal = "Science",

issn = "0036-8075",

publisher = "American Association for the Advancement of Science",

number = "6330",

}

Blondiaux, N, Moune, M, Desroses, M, Frita, R, Flipo, M, Mathys, V, Soetaert, K, Kiass, M, Delorme, V, Djaout, K, Trebosc, V, Kemmer, C, Wintjens, R, Wohlkönig, A, Antoine, R, Huot, L, Hot, D, Coscolla, M, Feldmann, J, Gagneux, S, Locht, C, Brodin, P, Gitzinger, M, Déprez, B, Willand, N & Baulard, AR 2017, 'reverse resistance', Science, vol. 355, no. 6330, pp. 1206-1211. https://doi.org/10.1126/science.aag1006

reverse resistance. / Blondiaux, Nicolas; Moune, Martin; Desroses, Matthieu; Frita, Rosangela; Flipo, Marion; Mathys, Vanessa; Soetaert, Karine; Kiass, Mehdi; Delorme, Vincent; Djaout, Kamel; Trebosc, Vincent; Kemmer, Christian; Wintjens, René; Wohlkönig, Alexandre; Antoine, Rudy; Huot, Ludovic; Hot, David; Coscolla, Mireia; Feldmann, Julia; Gagneux, Sebastien; Locht, Camille; Brodin, Priscille; Gitzinger, Marc; Déprez, Benoit; Willand, Nicolas; Baulard, Alain R.

In: Science, Vol. 355, No. 6330, 2017, p. 1206-1211.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - reverse resistance

AU - Blondiaux, Nicolas

AU - Moune, Martin

AU - Desroses, Matthieu

AU - Frita, Rosangela

AU - Flipo, Marion

AU - Mathys, Vanessa

AU - Soetaert, Karine

AU - Kiass, Mehdi

AU - Delorme, Vincent

AU - Djaout, Kamel

AU - Trebosc, Vincent

AU - Kemmer, Christian

AU - Wintjens, René

AU - Wohlkönig, Alexandre

AU - Antoine, Rudy

AU - Huot, Ludovic

AU - Hot, David

AU - Coscolla, Mireia

AU - Feldmann, Julia

AU - Gagneux, Sebastien

AU - Locht, Camille

AU - Brodin, Priscille

AU - Gitzinger, Marc

AU - Déprez, Benoit

AU - Willand, Nicolas

AU - Baulard, Alain R.

PY - 2017

Y1 - 2017

N2 - 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.

AB - 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.

UR - http://www.sciencemag.org/lookup/doi/10.1126/science.aag1006

UR - http://www.mendeley.com/research/reverse-resistance

U2 - 10.1126/science.aag1006

DO - 10.1126/science.aag1006

M3 - Article

C2 - 28302858

VL - 355

SP - 1206

EP - 1211

JO - Science

JF - Science

SN - 0036-8075

IS - 6330

ER -

reverse resistance

Abstract

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