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Chemical disarming of isoniazid resistance in Mycobacterium tuberculosis
- Source :
- Proceedings of the National Academy of Sciences. 116:10510-10517
- Publication Year :
- 2019
- Publisher :
- Proceedings of the National Academy of Sciences, 2019.
-
Abstract
- 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.
- Subjects :
- 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
Subjects
Details
- ISSN :
- 10916490 and 00278424
- Volume :
- 116
- Database :
- OpenAIRE
- Journal :
- Proceedings of the National Academy of Sciences
- Accession number :
- edsair.doi...........0fc38cc536017cb4fd2b8f71cbd16357
- Full Text :
- https://doi.org/10.1073/pnas.1818009116