IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v4y2013i1d10.1038_ncomms3748.html
   My bibliography  Save this article

Mechanism of inhibition of Mycobacterium tuberculosis antigen 85 by ebselen

Author

Listed:
  • Lorenza Favrot

    (University of Toledo)

  • Anna E. Grzegorzewicz

    (Mycobacteria Research Laboratories, Immunology and Pathology, Colorado State University)

  • Daniel H. Lajiness

    (University of Toledo)

  • Rachel K. Marvin

    (University of Toledo)

  • Julie Boucau

    (University of Toledo
    Present address: The Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts 02139, USA)

  • Dragan Isailovic

    (University of Toledo)

  • Mary Jackson

    (Mycobacteria Research Laboratories, Immunology and Pathology, Colorado State University)

  • Donald R. Ronning

    (University of Toledo)

Abstract

The increasing prevalence of drug-resistant tuberculosis highlights the need for identifying new antitubercular drugs that can treat these infections. The antigen 85 (Ag85) complex has emerged as an intriguing mycobacterial drug target due to its central role in synthesizing major components of the inner and outer leaflets of the mycobacterial outer membrane. Here we identify ebselen (EBS) as a potent inhibitor of the Mycobacterium tuberculosis Ag85 complex. Mass spectrometry data show that EBS binds covalently to a cysteine residue (C209) located near the Ag85C active site. The crystal structure of Ag85C in the presence of EBS shows that C209 modification restructures the active site, thereby disrupting the hydrogen-bonded network within the active site that is essential for enzymatic activity. C209 mutations display marked decreases in enzymatic activity. These data suggest that compounds using this mechanism of action will strongly inhibit the Ag85 complex and minimize the selection of drug resistance.

Suggested Citation

  • Lorenza Favrot & Anna E. Grzegorzewicz & Daniel H. Lajiness & Rachel K. Marvin & Julie Boucau & Dragan Isailovic & Mary Jackson & Donald R. Ronning, 2013. "Mechanism of inhibition of Mycobacterium tuberculosis antigen 85 by ebselen," Nature Communications, Nature, vol. 4(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:4:y:2013:i:1:d:10.1038_ncomms3748
    DOI: 10.1038/ncomms3748
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/ncomms3748
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/ncomms3748?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
    ---><---

    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:4:y:2013:i:1:d:10.1038_ncomms3748. 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.