期刊
SCIENCE
卷 355, 期 6330, 页码 1206-1211出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.aag1006
关键词
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资金
- l'Agence Nationale de la Recherche (ANR), France [Tea-4-Two, ANR-14-CE14-0027-01, ANR-10-EQPX-04-01]
- EU grants ERC-STG INTRACELLTB [26090L, 12001407]
- PRIM (NewBio4Tb)
- European Research Council [309540-EVODRTB]
- SystemsX.ch
- Institut National de la Sante et de la Recherche Medicale
- Universite de Lille
- Institut Pasteur de Lille
- Centre National de la Recherche Scientifique
- Region Hauts-de-France [12000080]
- Societe d'Acceleration du Transfert de Technologie Nord
- PRIM (NewBio4Tro)
- EU [260872]
- Marie Curie Initial Training Network [ITN-2013-607694-Translocation]
- Unite Mixte de Recherche UMR [8199]
- Lille Integrated Genomics Network for Advanced Personalized Medicine (LIGAN-PM) Genomics platform (Lille, France) [3508, ANR-10-LABX-46]
- Agence Nationale de la Recherche (ANR) Erg Apex [ANR-10-EQPX-07-01]
- Fonds Europeen de Developpement Regional
- Region Hauts-de-France
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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