Targeting protein biotinylation enhances tuberculosis chemotherapy

Divya Tiwari, Sae Woong Park, Maram M. Essawy, Surendra Dawadi, Alan Mason, Madhumitha Nandakumar, Matthew Zimmerman, Marizel Mina, Hsin Pin Ho, Curtis A. Engelhart, Thomas Ioerger, James C. Sacchettini, Kyu Rhee, Sabine Ehrt, Courtney C. Aldrich, Véronique Dartois, Dirk Schnappinger

Research output: Contribution to journalArticle

10 Scopus citations

Abstract

Successful drug treatment for tuberculosis (TB) depends on the unique contributions of its component drugs. Drug resistance poses a threat to the efficacy of individual drugs and the regimens to which they contribute. Biologically and chemically validated targets capable of replacing individual components of current TB chemotherapy are a major unmet need in TB drug development. We demonstrate that chemical inhibition of the bacterial biotin protein ligase (BPL) with the inhibitor Bio-AMS (5′-[N-(d-biotinoyl)sulfamoyl]amino-5′-deoxyadenosine) killed Mycobacterium tuberculosis (Mtb), the bacterial pathogen causing TB. We also show that genetic silencing of BPL eliminated the pathogen efficiently from mice during acute and chronic infection with Mtb. Partial chemical inactivation of BPL increased the potency of two first-line drugs, rifampicin and ethambutol, and genetic interference with protein biotinylation accelerated clearance of Mtb from mouse lungs and spleens by rifampicin. These studies validate BPL as a potential drug target that could serve as an alternate frontline target in the development of new drugs against Mtb.

Original languageEnglish (US)
Article numbereaal1803
JournalScience Translational Medicine
Volume10
Issue number438
DOIs
StatePublished - Apr 25 2018

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

Fingerprint Dive into the research topics of 'Targeting protein biotinylation enhances tuberculosis chemotherapy'. Together they form a unique fingerprint.

  • Cite this

    Tiwari, D., Park, S. W., Essawy, M. M., Dawadi, S., Mason, A., Nandakumar, M., Zimmerman, M., Mina, M., Ho, H. P., Engelhart, C. A., Ioerger, T., Sacchettini, J. C., Rhee, K., Ehrt, S., Aldrich, C. C., Dartois, V., & Schnappinger, D. (2018). Targeting protein biotinylation enhances tuberculosis chemotherapy. Science Translational Medicine, 10(438), [eaal1803]. https://doi.org/10.1126/scitranslmed.aal1803