Chemical disarming of isoniazid resistance in Mycobacterium tuberculosis
| Autor: | Martina Kulén, Christer Larsson, Fredrik Almqvist, K. Syam Krishnan, Erik Chorell, James A. D. Good, Mette R. Hansen, Gregory A. Harrison, Dennis X. Zhu, Jonathan Livny, Scott J. Hultgren, Kelly Flentie, Christina L. Stallings, Anders E. G. Lindgren, Leslie A. Weiss, Torbjörn Wixe, Hasan Tükenmez, Andrew G. Cairns, Christoffer Bengtsson, Souvik Sarkar, Samantha D. Solomon, Miranda E. Schene, Rachel L. Kinsella |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Multidisciplinary Tuberculosis medicine.drug_class 030106 microbiology Antibiotics Isoniazid Drug resistance biochemical phenomena metabolism and nutrition respiratory system Biology bacterial infections and mycoses biology.organism_classification medicine.disease Microbiology Mycobacterium tuberculosis 03 medical and health sciences 030104 developmental biology Antibiotic resistance Drug tolerance medicine Pathogen medicine.drug |
| Zdroj: | Proceedings of the National Academy of Sciences. 116:10510-10517 |
| ISSN: | 1091-6490 0027-8424 |
| Popis: | Mycobacterium tuberculosis ( Mtb ) killed more people in 2017 than any other single infectious agent. This dangerous pathogen is able to withstand stresses imposed by the immune system and tolerate exposure to antibiotics, resulting in persistent infection. The global tuberculosis (TB) epidemic has been exacerbated by the emergence of mutant strains of Mtb that are resistant to frontline antibiotics. Thus, both phenotypic drug tolerance and genetic drug resistance are major obstacles to successful TB therapy. Using a chemical approach to identify compounds that block stress and drug tolerance, as opposed to traditional screens for compounds that kill Mtb , we identified a small molecule, C10, that blocks tolerance to oxidative stress, acid stress, and the frontline antibiotic isoniazid (INH). In addition, we found that C10 prevents the selection for INH-resistant mutants and restores INH sensitivity in otherwise INH-resistant Mtb strains harboring mutations in the katG gene, which encodes the enzyme that converts the prodrug INH to its active form. Through mechanistic studies, we discovered that C10 inhibits Mtb respiration, revealing a link between respiration homeostasis and INH sensitivity. Therefore, by using C10 to dissect Mtb persistence, we discovered that INH resistance is not absolute and can be reversed. |
| Databáze: | OpenAIRE |
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