Mechanism of inhibition of Mycobacterium tuberculosis antigen 85 by ebselen

Lorenza Favrot, Anna E. Grzegorzewicz, Daniel H. Lajiness, Rachel K. Marvin, Julie Boucau, Dragan Isailovic, Mary Jackson and Donald R. Ronning ()
Additional contact information
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
Dragan Isailovic: University of Toledo
Mary Jackson: Mycobacteria Research Laboratories, Immunology and Pathology, Colorado State University
Donald R. Ronning: University of Toledo

Nature Communications, 2013, vol. 4, issue 1, 1-10

Abstract: 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.

Date: 2013
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/ncomms3748 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:4:y:2013:i:1:d:10.1038_ncomms3748

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/ncomms3748

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().