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Chemical disarming of isoniazid resistance in Mycobacterium tuberculosis
Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).ORCID-id: 0000-0002-2259-6883
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2019 (Engelska)Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 116, nr 21, s. 10510-10517Artikel i tidskrift (Refereegranskat) 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.

Ort, förlag, år, upplaga, sidor
The National Academy of Scionces of the United States of America , 2019. Vol. 116, nr 21, s. 10510-10517
Nyckelord [en]
Mycobacterium tuberculosis, drug tolerance, antibiotic resistance, isoniazid, respiration
Nationell ämneskategori
Infektionsmedicin
Identifikatorer
URN: urn:nbn:se:umu:diva-159857DOI: 10.1073/pnas.1818009116ISI: 000468403400054PubMedID: 31061116OAI: oai:DiVA.org:umu-159857DiVA, id: diva2:1322243
Forskningsfinansiär
VetenskapsrådetKnut och Alice Wallenbergs StiftelseStiftelsen för strategisk forskning (SSF)KempestiftelsernaNIH (National Institute of Health)Tillgänglig från: 2019-06-10 Skapad: 2019-06-10 Senast uppdaterad: 2019-06-10Bibliografiskt granskad

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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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Institutionen för molekylärbiologi (Medicinska fakulteten)Kemiska institutionenUmeå Centre for Microbial Research (UCMR)Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet)
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Proceedings of the National Academy of Sciences of the United States of America
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