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Chemical disarming of isoniazid resistance in Mycobacterium tuberculosis
Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).ORCID iD: 0000-0002-2259-6883
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2019 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 116, no 21, p. 10510-10517Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
The National Academy of Scionces of the United States of America , 2019. Vol. 116, no 21, p. 10510-10517
Keywords [en]
Mycobacterium tuberculosis, drug tolerance, antibiotic resistance, isoniazid, respiration
National Category
Infectious Medicine
Identifiers
URN: urn:nbn:se:umu:diva-159857DOI: 10.1073/pnas.1818009116ISI: 000468403400054PubMedID: 31061116OAI: oai:DiVA.org:umu-159857DiVA, id: diva2:1322243
Funder
Swedish Research CouncilKnut and Alice Wallenberg FoundationSwedish Foundation for Strategic Research The Kempe FoundationsNIH (National Institute of Health)Available from: 2019-06-10 Created: 2019-06-10 Last updated: 2019-06-10Bibliographically approved

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Tükenmez, HasanGood, James A. D.Hansen, Mette R.Cairns, Andrew G.Kulén, MartinaWixe, TorbjörnLindgren, Anders E. G.Chorell, ErikBengtsson, ChristofferLarsson, ChristerAlmqvist, Fredrik

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Tükenmez, HasanGood, James A. D.Hansen, Mette R.Cairns, Andrew G.Kulén, MartinaWixe, TorbjörnLindgren, Anders E. G.Chorell, ErikBengtsson, ChristofferLarsson, ChristerAlmqvist, Fredrik
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Department of Molecular Biology (Faculty of Medicine)Department of ChemistryUmeå Centre for Microbial Research (UCMR)Department of Molecular Biology (Faculty of Science and Technology)
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Proceedings of the National Academy of Sciences of the United States of America
Infectious Medicine

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