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

Blondiaux, Nicolas and Moune, Martin and Desroses, Matthieu and Frita, Rosangela and Flipo, Marion and Mathys, Vanessa and Soetaert, Karine and Kiass, Mehdi and Delorme, Vincent and Djaout, Kamel and Trebosc, Vincent and Kemmer, Christian and Wintjens, René and Wohlkönig, Alexandre and Antoine, Rudy and Huot, Ludovic and Hot, David and Coscolla, Mireia and Feldmann, Julia and Gagneux, Sebastien and Locht, Camille and Brodin, Priscille and Gitzinger, Marc and Déprez, Benoit and Willand, Nicolas and Baulard, Alain R.. (2017) Reversion of antibiotic resistance in Mycobacterium tuberculosis by spiroisoxazoline SMARt-420. Science, 355 (6330). pp. 1206-1211.

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Official URL: http://edoc.unibas.ch/54704/

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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.
Faculties and Departments:09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH)
09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) > Department of Medical Parasitology and Infection Biology > Tuberculosis Research (Gagneux)
UniBasel Contributors:Coscollá, Mireja
Item Type:Article, refereed
Publisher:American Association for the Advancement of Science
ISSN:0036-8075
e-ISSN:1095-9203
Note:Publication type according to Uni Basel Research Database: Journal article
Identification Number:
Last Modified:25 Apr 2017 12:19
Deposited On:25 Apr 2017 12:19

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