Chemical disarming of isoniazid resistance in Mycobacterium tuberculosis

Kelly Flentie, Gregory A. Harrison, Hasan Tükenmez, Jonathan Livny, James A.D. Good, Souvik Sarkar, Dennis X. Zhu, Rachel L. Kinsella, Leslie A. Weiss, Samantha D. Solomon, Miranda E. Schene, Mette R. Hansen, Andrew G. Cairns, Martina Kulén, Torbjörn Wixe, Anders E.G. Lindgren, Erik Chorell, Christoffer Bengtsson, K. Syam Krishnan, Scott J. HultgrenChrister Larsson, Fredrik Almqvist, Christina L. Stallings

Research output: Contribution to journalArticle

9 Scopus citations

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.

Original languageEnglish
Pages (from-to)10510-10517
Number of pages8
JournalProceedings of the National Academy of Sciences of the United States of America
Volume116
Issue number21
DOIs
StatePublished - Jan 1 2019

Keywords

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

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    Flentie, K., Harrison, G. A., Tükenmez, H., Livny, J., Good, J. A. D., Sarkar, S., Zhu, D. X., Kinsella, R. L., Weiss, L. A., Solomon, S. D., Schene, M. E., Hansen, M. R., Cairns, A. G., Kulén, M., Wixe, T., Lindgren, A. E. G., Chorell, E., Bengtsson, C., Krishnan, K. S., ... Stallings, C. L. (2019). Chemical disarming of isoniazid resistance in Mycobacterium tuberculosis. Proceedings of the National Academy of Sciences of the United States of America, 116(21), 10510-10517. https://doi.org/10.1073/pnas.1818009116