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High efficacy of the F-ATP synthase inhibitor TBAJ-5307 against nontuberculous mycobacteria in vitro and in vivo.
Ragunathan, Priya; Sae-Lao, Patcharaporn; Hamela, Claire; Alcaraz, Matthéo; Krah, Alexander; Poh, Wee Han; Ern Pee, Carmen Jia; Hou Lim, Albert Yick; Rice, Scott A; Pethe, Kevin; Bond, Peter J; Dick, Thomas; Kremer, Laurent; Bates, Roderick W; Grüber, Gerhard.
Afiliación
  • Ragunathan P; School of Biological Sciences, Nanyang Technological University, Singapore.
  • Sae-Lao P; School of Chemistry, Chemical Engineering and Biotechnology, Nanyang Technological University, Singapore.
  • Hamela C; Centre National de la Recherche Scientifique UMR 9004, Institut de Recherche en Infectiologie de Montpellier (IRIM), Université de Montpellier, Montpellier, France.
  • Alcaraz M; Centre National de la Recherche Scientifique UMR 9004, Institut de Recherche en Infectiologie de Montpellier (IRIM), Université de Montpellier, Montpellier, France.
  • Krah A; Bioinformatics Institute, Agency for Science, Technology and Research (A∗STAR), Singapore.
  • Poh WH; Singapore Centre for Environmental Life Sciences Engineering, Nanyang Technological University, Singapore.
  • Ern Pee CJ; Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore.
  • Hou Lim AY; Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore; Department for Respiratory and Critical Care Medicine, Tan Tock Seng Hospital, Singapore.
  • Rice SA; School of Biological Sciences, Nanyang Technological University, Singapore; Bioinformatics Institute, Agency for Science, Technology and Research (A∗STAR), Singapore; Microbiomes for One Systems Health and Agriculture and Food, CSIRO, Westmead, New South Wales, Australia.
  • Pethe K; School of Biological Sciences, Nanyang Technological University, Singapore; Bioinformatics Institute, Agency for Science, Technology and Research (A∗STAR), Singapore; Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore; National Centre for Infectious Diseases (NCID),
  • Bond PJ; Bioinformatics Institute, Agency for Science, Technology and Research (A∗STAR), Singapore.
  • Dick T; Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, New Jersey, USA; Department of Medical Sciences, Hackensack Meridian School of Medicine, Nutley, New Jersey, USA; Department of Microbiology and Immunology, Georgetown University, Washington, District of Columbia, USA.
  • Kremer L; Centre National de la Recherche Scientifique UMR 9004, Institut de Recherche en Infectiologie de Montpellier (IRIM), Université de Montpellier, Montpellier, France; INSERM, IRIM, Montpellier, France. Electronic address: Laurent.kremer@irim.cnrs.fr.
  • Bates RW; School of Chemistry, Chemical Engineering and Biotechnology, Nanyang Technological University, Singapore. Electronic address: Roderick@ntu.edu.sg.
  • Grüber G; School of Biological Sciences, Nanyang Technological University, Singapore; Bioinformatics Institute, Agency for Science, Technology and Research (A∗STAR), Singapore. Electronic address: ggrueber@ntu.edu.sg.
J Biol Chem ; 300(2): 105618, 2024 Feb.
Article en En | MEDLINE | ID: mdl-38176652
ABSTRACT
The F1FO-ATP synthase engine is essential for viability and growth of nontuberculous mycobacteria (NTM) by providing the biological energy ATP and keeping ATP homeostasis under hypoxic stress conditions. Here, we report the discovery of the diarylquinoline TBAJ-5307 as a broad spectrum anti-NTM inhibitor, targeting the FO domain of the engine and preventing rotation and proton translocation. TBAJ-5307 is active at low nanomolar concentrations against fast- and slow-growing NTM as well as clinical isolates by depleting intrabacterial ATP. As demonstrated for the fast grower Mycobacterium abscessus, the compound is potent in vitro and in vivo, without inducing toxicity. Combining TBAJ-5307 with anti-NTM antibiotics or the oral tebipenem-avibactam pair showed attractive potentiation. Furthermore, the TBAJ-5307-tebipenem-avibactam cocktail kills the pathogen, suggesting a novel oral combination for the treatment of NTM lung infections.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Inhibidores Enzimáticos / Diarilquinolinas / Antibacterianos / Micobacterias no Tuberculosas / Infecciones por Mycobacterium no Tuberculosas Límite: Humans Idioma: En Revista: J Biol Chem Año: 2024 Tipo del documento: Article País de afiliación: Singapur Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Inhibidores Enzimáticos / Diarilquinolinas / Antibacterianos / Micobacterias no Tuberculosas / Infecciones por Mycobacterium no Tuberculosas Límite: Humans Idioma: En Revista: J Biol Chem Año: 2024 Tipo del documento: Article País de afiliación: Singapur Pais de publicación: Estados Unidos