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Chemical disarming of isoniazid resistance in Mycobacterium tuberculosis.
Flentie, Kelly; Harrison, Gregory A; Tükenmez, Hasan; Livny, Jonathan; Good, James A D; Sarkar, Souvik; Zhu, Dennis X; Kinsella, Rachel L; Weiss, Leslie A; Solomon, Samantha D; Schene, Miranda E; Hansen, Mette R; Cairns, Andrew G; Kulén, Martina; Wixe, Torbjörn; Lindgren, Anders E G; Chorell, Erik; Bengtsson, Christoffer; Krishnan, K Syam; Hultgren, Scott J; Larsson, Christer; Almqvist, Fredrik; Stallings, Christina L.
Afiliación
  • Flentie K; Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110.
  • Harrison GA; Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110.
  • Tükenmez H; Department of Molecular Biology, Umeå University, SE-90187 Umeå, Sweden.
  • Livny J; Infectious Disease and Microbiome Program, Broad Institute, Cambridge, MA 02142.
  • Good JAD; Umeå Centre for Microbial Research, Umeå University, SE-90187 Umeå, Sweden.
  • Sarkar S; Department of Chemistry, Umeå University, SE-90187 Umeå, Sweden.
  • Zhu DX; Umeå Centre for Microbial Research, Umeå University, SE-90187 Umeå, Sweden.
  • Kinsella RL; Department of Chemistry, Umeå University, SE-90187 Umeå, Sweden.
  • Weiss LA; Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110.
  • Solomon SD; Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110.
  • Schene ME; Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110.
  • Hansen MR; Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110.
  • Cairns AG; Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110.
  • Kulén M; Umeå Centre for Microbial Research, Umeå University, SE-90187 Umeå, Sweden.
  • Wixe T; Department of Chemistry, Umeå University, SE-90187 Umeå, Sweden.
  • Lindgren AEG; Umeå Centre for Microbial Research, Umeå University, SE-90187 Umeå, Sweden.
  • Chorell E; Department of Chemistry, Umeå University, SE-90187 Umeå, Sweden.
  • Bengtsson C; Umeå Centre for Microbial Research, Umeå University, SE-90187 Umeå, Sweden.
  • Krishnan KS; Department of Chemistry, Umeå University, SE-90187 Umeå, Sweden.
  • Hultgren SJ; Umeå Centre for Microbial Research, Umeå University, SE-90187 Umeå, Sweden.
  • Larsson C; Department of Chemistry, Umeå University, SE-90187 Umeå, Sweden.
  • Almqvist F; Umeå Centre for Microbial Research, Umeå University, SE-90187 Umeå, Sweden.
  • Stallings CL; Department of Chemistry, Umeå University, SE-90187 Umeå, Sweden.
Proc Natl Acad Sci U S A ; 116(21): 10510-10517, 2019 05 21.
Article en En | MEDLINE | ID: mdl-31061116
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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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Farmacorresistencia Bacteriana / Isoniazida / Mycobacterium tuberculosis / Antituberculosos Idioma: En Revista: Proc Natl Acad Sci U S A Año: 2019 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Farmacorresistencia Bacteriana / Isoniazida / Mycobacterium tuberculosis / Antituberculosos Idioma: En Revista: Proc Natl Acad Sci U S A Año: 2019 Tipo del documento: Article Pais de publicación: Estados Unidos