2. Academic Validation
  3. High efficacy of the F-ATP synthase inhibitor TBAJ-5307 against non-tuberculous mycobacteria in vitro and in vivo

High efficacy of the F-ATP synthase inhibitor TBAJ-5307 against non-tuberculous mycobacteria in vitro and in vivo

  • J Biol Chem. 2024 Jan 2:105618. doi: 10.1016/j.jbc.2023.105618.
Priya Ragunathan 1,  Patcharaporn Sae-Lao 2,  Claire Hamela 3,  Matthéo Alcaraz 3,  Alexander Krah 4,  Wee Han Poh 5,  Carmen Jia Ern Pee 6,  Albert Yick Hou Lim 7,  Scott A Rice 8,  Kevin Pethe 9,  Peter John Bond 4,  Thomas Dick 10,  Laurent Kremer 11,  Roderick W Bates 12,  Gerhard Grüber 13
Affiliations

Affiliations

  • 1 School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551.
  • 2 School of Chemistry, Chemical Engineering and Biotechnology, Nanyang Technological University, 21 Nanyang Link, Singapore 637371.
  • 3 Centre National de la Recherche Scientifique UMR 9004, Institut de Recherche en Infectiologie de Montpellier (IRIM), Université de Montpellier, 1919 route de Mende, 34293, Montpellier, France.
  • 4 Bioinformatics Institute, Agency for Science, Technology and Research (A*STAR), 30 Biopolis Str., #07-01 Matrix, Singapore 138671.
  • 5 Singapore Centre for Environmental Life Sciences Engineering, Nanyang Technological University, Singapore 637551.
  • 6 Lee Kong Chian School of Medicine, Nanyang Technological University, Experimental Medicine Building, Singapore 636921.
  • 7 Lee Kong Chian School of Medicine, Nanyang Technological University, Experimental Medicine Building, Singapore 636921; Department for Respiratory and Critical Care Medicine, Tan Tock Seng Hospital, Singapore 308433.
  • 8 School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551; Bioinformatics Institute, Agency for Science, Technology and Research (A*STAR), 30 Biopolis Str., #07-01 Matrix, Singapore 138671; Microbiomes for One Systems Health and Agriculture and Food, CSIRO, Westmead NSW, Australia.
  • 9 School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551; Bioinformatics Institute, Agency for Science, Technology and Research (A*STAR), 30 Biopolis Str., #07-01 Matrix, Singapore 138671; Lee Kong Chian School of Medicine, Nanyang Technological University, Experimental Medicine Building, Singapore 636921; National Centre for Infectious Diseases (NCID), 16 Jalan Tan Tock Seng, Singapore 308442.
  • 10 Center for Discovery and Innovation, Hackensack Meridian Health, 340 Kingsland Street, Nutley, NJ 07110, USA; Department of Medical Sciences, Hackensack Meridian School of Medicine, 123 Metro Boulevard, Nutley, NJ 07110, USA; Department of Microbiology and Immunology, Georgetown University, 3900 Reservoir Road NW Medical-Dental Building, Washington, DC 20007, USA.
  • 11 Centre National de la Recherche Scientifique UMR 9004, Institut de Recherche en Infectiologie de Montpellier (IRIM), Université de Montpellier, 1919 route de Mende, 34293, Montpellier, France; INSERM, IRIM, 34293 Montpellier, France. Electronic address: Laurent.kremer@irim.cnrs.fr.
  • 12 School of Chemistry, Chemical Engineering and Biotechnology, Nanyang Technological University, 21 Nanyang Link, Singapore 637371. Electronic address: Roderick@ntu.edu.sg.
  • 13 School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551; Bioinformatics Institute, Agency for Science, Technology and Research (A*STAR), 30 Biopolis Str., #07-01 Matrix, Singapore 138671. Electronic address: ggrueber@ntu.edu.sg.
PMID: 38176652 DOI: 10.1016/j.jbc.2023.105618
Abstract

The F1FO-ATP synthase engine is essential for viability and growth of non-tuberculous 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.

Keywords

ATP synthesis; Mycobacteria; antibiotics; bacterial pathogenesis; membrane protein; non-tuberculosis mycobacterium.

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