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Chemical disarming of isoniazid resistance in Mycobacterium tuberculosis.

Authors
  • Flentie, Kelly1
  • Harrison, Gregory A1
  • Tükenmez, Hasan2
  • Livny, Jonathan3
  • Good, James A D4, 5
  • Sarkar, Souvik4, 5
  • Zhu, Dennis X1
  • Kinsella, Rachel L1
  • Weiss, Leslie A1
  • Solomon, Samantha D1
  • Schene, Miranda E1
  • Hansen, Mette R4, 5
  • Cairns, Andrew G4, 5
  • Kulén, Martina4, 5
  • Wixe, Torbjörn4, 5
  • Lindgren, Anders E G4, 5
  • Chorell, Erik1, 4, 5
  • Bengtsson, Christoffer4, 5
  • Krishnan, K Syam4, 5
  • Hultgren, Scott J1, 6
  • And 3 more
  • 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. , (Sweden)
  • 3 Infectious Disease and Microbiome Program, Broad Institute, Cambridge, MA 02142.
  • 4 Umeå Centre for Microbial Research, Umeå University, SE-90187 Umeå, Sweden. , (Sweden)
  • 5 Department of Chemistry, Umeå University, SE-90187 Umeå, Sweden. , (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; [email protected] [email protected] , (Sweden)
  • 8 Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110; [email protected] [email protected]
Type
Published Article
Journal
Proceedings of the National Academy of Sciences
Publisher
Proceedings of the National Academy of Sciences
Publication Date
May 21, 2019
Volume
116
Issue
21
Pages
10510–10517
Identifiers
DOI: 10.1073/pnas.1818009116
PMID: 31061116
Source
Medline
Keywords
Language
English
License
Unknown

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.

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