| Literature DB >> 28302858 |
Nicolas Blondiaux1, Martin Moune1, Matthieu Desroses2,3, Rosangela Frita1, Marion Flipo2, Vanessa Mathys4, Karine Soetaert4, Mehdi Kiass4, Vincent Delorme1,5, Kamel Djaout1, Vincent Trebosc6,7, Christian Kemmer6, René Wintjens8, Alexandre Wohlkönig9,10, Rudy Antoine1, Ludovic Huot1, David Hot1, Mireia Coscolla11,12, Julia Feldmann11,12, Sebastien Gagneux11,12, Camille Locht1, Priscille Brodin1, Marc Gitzinger6, Benoit Déprez13, Nicolas Willand13, Alain R Baulard14.
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.Entities:
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Year: 2017 PMID： 28302858 DOI： 10.1126/science.aag1006
Source DB: PubMed Journal: Science ISSN： 0036-8075 Impact factor: 47.728