IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v11y2020i1d10.1038_s41467-020-19959-4.html
   My bibliography  Save this article

Bedaquiline reprograms central metabolism to reveal glycolytic vulnerability in Mycobacterium tuberculosis

Author

Listed:
  • Jared S. Mackenzie

    (Africa Health Research Institute)

  • Dirk A. Lamprecht

    (Janssen Pharmaceutica, Global Public Health)

  • Rukaya Asmal

    (Africa Health Research Institute)

  • John H. Adamson

    (Africa Health Research Institute)

  • Khushboo Borah

    (Faculty of Health and Medical Sciences, University of Surrey)

  • Dany J. V. Beste

    (Faculty of Health and Medical Sciences, University of Surrey)

  • Bei Shi Lee

    (Nanyang Technological University)

  • Kevin Pethe

    (Nanyang Technological University
    Lee Kong Chian School of Medicine, Nanyang Technological University)

  • Simon Rousseau

    (Texas A&M University, Department of Biochemistry and Biophysics)

  • Inna Krieger

    (Texas A&M University, Department of Biochemistry and Biophysics)

  • James C. Sacchettini

    (Texas A&M University, Department of Biochemistry and Biophysics)

  • Joel N. Glasgow

    (University of Alabama at Birmingham)

  • Adrie J. C. Steyn

    (Africa Health Research Institute
    University of Alabama at Birmingham
    Center for AIDS Research and Center for Free Radical Biology, University of Alabama at Birmingham)

Abstract

The approval of bedaquiline (BDQ) for the treatment of tuberculosis has generated substantial interest in inhibiting energy metabolism as a therapeutic paradigm. However, it is not known precisely how BDQ triggers cell death in Mycobacterium tuberculosis (Mtb). Using 13C isotopomer analysis, we show that BDQ-treated Mtb redirects central carbon metabolism to induce a metabolically vulnerable state susceptible to genetic disruption of glycolysis and gluconeogenesis. Metabolic flux profiles indicate that BDQ-treated Mtb is dependent on glycolysis for ATP production, operates a bifurcated TCA cycle by increasing flux through the glyoxylate shunt, and requires enzymes of the anaplerotic node and methylcitrate cycle. Targeting oxidative phosphorylation (OXPHOS) with BDQ and simultaneously inhibiting substrate level phosphorylation via genetic disruption of glycolysis leads to rapid sterilization. Our findings provide insight into the metabolic mechanism of BDQ-induced cell death and establish a paradigm for the development of combination therapies that target OXPHOS and glycolysis.

Suggested Citation

  • Jared S. Mackenzie & Dirk A. Lamprecht & Rukaya Asmal & John H. Adamson & Khushboo Borah & Dany J. V. Beste & Bei Shi Lee & Kevin Pethe & Simon Rousseau & Inna Krieger & James C. Sacchettini & Joel N., 2020. "Bedaquiline reprograms central metabolism to reveal glycolytic vulnerability in Mycobacterium tuberculosis," Nature Communications, Nature, vol. 11(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-19959-4
    DOI: 10.1038/s41467-020-19959-4
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-020-19959-4
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-020-19959-4?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    Citations

    Citations are extracted by the CitEc Project, subscribe to its RSS feed for this item.
    as


    Cited by:

    1. XinYue Wang & William J. Jowsey & Chen-Yi Cheung & Caitlan J. Smart & Hannah R. Klaus & Noon EJ Seeto & Natalie JE Waller & Michael T. Chrisp & Amanda L. Peterson & Boatema Ofori-Anyinam & Emily Stron, 2024. "Whole genome CRISPRi screening identifies druggable vulnerabilities in an isoniazid resistant strain of Mycobacterium tuberculosis," Nature Communications, Nature, vol. 15(1), pages 1-18, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-19959-4. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    We have no bibliographic references for this item. You can help adding them by using this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.