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Proc Natl Acad Sci U S A. 2019 May 21;116(21):10510-10517. doi: 10.1073/pnas.1818009116. Epub 2019 May 6.

Chemical disarming of isoniazid resistance in Mycobacterium tuberculosis.

Author information

1
Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110.
2
Department of Molecular Biology, Umeå University, SE-90187 Umeå, Sweden.
3
Infectious Disease and Microbiome Program, Broad Institute, Cambridge, MA 02142.
4
Umeå Centre for Microbial Research, Umeå University, SE-90187 Umeå, Sweden.
5
Department of Chemistry, Umeå University, SE-90187 Umeå, Sweden.
6
Center for Women's Infectious Disease Research, Washington University School of Medicine, St. Louis, MO 63110.
7
Umeå Centre for Microbial Research, Umeå University, SE-90187 Umeå, Sweden; fredrik.almqvist@umu.se stallings@wustl.edu.
8
Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110; fredrik.almqvist@umu.se stallings@wustl.edu.

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.

KEYWORDS:

Mycobacterium tuberculosis; antibiotic resistance; drug tolerance; isoniazid; respiration

PMID:
31061116
PMCID:
PMC6535022
[Available on 2019-11-06]
DOI:
10.1073/pnas.1818009116

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