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Delayed bactericidal response of Mycobacterium tuberculosis to bedaquiline involves remodelling of bacterial metabolism

Author

Listed:
  • Anil Koul

    (Infectious diseases and vaccines therapeutic area, Janssen Research & Development, Johnson & Johnson Pharmaceuticals)

  • Luc Vranckx

    (Infectious diseases and vaccines therapeutic area, Janssen Research & Development, Johnson & Johnson Pharmaceuticals)

  • Neeraj Dhar

    (Swiss Federal Institute of Technology in Lausanne (EPFL), School of Life Sciences)

  • Hinrich W.H. Göhlmann

    (CREATe, Janssen Research & Development, Johnson & Johnson Pharmaceuticals)

  • Emre Özdemir

    (Swiss Federal Institute of Technology in Lausanne (EPFL), School of Life Sciences)

  • Jean-Marc Neefs

    (CREATe, Janssen Research & Development, Johnson & Johnson Pharmaceuticals)

  • Melanie Schulz

    (University of Southern Denmark)

  • Ping Lu

    (AIMMS, VU University Amsterdam)

  • Ejvind Mørtz

    (Alphalyse A/S, Unsbjergvej 4, DK-5220 Odense SØ, Denmark)

  • John D. McKinney

    (Swiss Federal Institute of Technology in Lausanne (EPFL), School of Life Sciences)

  • Koen Andries

    (Infectious diseases and vaccines therapeutic area, Janssen Research & Development, Johnson & Johnson Pharmaceuticals)

  • Dirk Bald

    (AIMMS, VU University Amsterdam)

Abstract

Bedaquiline (BDQ), an ATP synthase inhibitor, is the first drug to be approved for treatment of multidrug-resistant tuberculosis in decades. Though BDQ has shown excellent efficacy in clinical trials, its early bactericidal activity during the first week of chemotherapy is minimal. Here, using microfluidic devices and time-lapse microscopy of Mycobacterium tuberculosis, we confirm the absence of significant bacteriolytic activity during the first 3–4 days of exposure to BDQ. BDQ-induced inhibition of ATP synthesis leads to bacteriostasis within hours after drug addition. Transcriptional and proteomic analyses reveal that M. tuberculosis responds to BDQ by induction of the dormancy regulon and activation of ATP-generating pathways, thereby maintaining bacterial viability during initial drug exposure. BDQ-induced bacterial killing is significantly enhanced when the mycobacteria are grown on non-fermentable energy sources such as lipids (impeding ATP synthesis via glycolysis). Our results show that BDQ exposure triggers a metabolic remodelling in mycobacteria, thereby enabling transient bacterial survival.

Suggested Citation

  • Anil Koul & Luc Vranckx & Neeraj Dhar & Hinrich W.H. Göhlmann & Emre Özdemir & Jean-Marc Neefs & Melanie Schulz & Ping Lu & Ejvind Mørtz & John D. McKinney & Koen Andries & Dirk Bald, 2014. "Delayed bactericidal response of Mycobacterium tuberculosis to bedaquiline involves remodelling of bacterial metabolism," Nature Communications, Nature, vol. 5(1), pages 1-10, May.
  • Handle: RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms4369
    DOI: 10.1038/ncomms4369
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    Cited by:

    1. Boatema Ofori-Anyinam & Meagan Hamblin & Miranda L. Coldren & Barry Li & Gautam Mereddy & Mustafa Shaikh & Avi Shah & Courtney Grady & Navpreet Ranu & Sean Lu & Paul C. Blainey & Shuyi Ma & James J. C, 2024. "Catalase activity deficiency sensitizes multidrug-resistant Mycobacterium tuberculosis to the ATP synthase inhibitor bedaquiline," Nature Communications, Nature, vol. 15(1), pages 1-13, December.

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