2. Academic Validation
  3. Targeting protein biotinylation enhances tuberculosis chemotherapy

Targeting protein biotinylation enhances tuberculosis chemotherapy

  • Sci Transl Med. 2018 Apr 25;10(438):eaal1803. doi: 10.1126/scitranslmed.aal1803.
Divya Tiwari 1,  Sae Woong Park 1,  Maram M Essawy 2,  Surendra Dawadi 2,  Alan Mason 3,  Madhumitha Nandakumar 4,  Matthew Zimmerman 3,  Marizel Mina 3,  Hsin Pin Ho 3,  Curtis A Engelhart 1,  Thomas Ioerger 5,  James C Sacchettini 6,  Kyu Rhee 4,  Sabine Ehrt 1,  Courtney C Aldrich 2,  Véronique Dartois 7 8,  Dirk Schnappinger 9
Affiliations

Affiliations

  • 1 Department of Microbiology and Immunology, Weill Cornell Medical College, New York, NY 10021, USA.
  • 2 Department of Medicinal Chemistry, University of Minnesota, 308 Harvard Street Southeast, 8-174 WDH, Minneapolis, MN 55455, USA.
  • 3 Public Health Research Institute, New Jersey Medical School, Rutgers, State University of New Jersey, Newark, NJ 07103, USA.
  • 4 Weill Department of Medicine, Weill Cornell Medical College, New York, NY 10021, USA.
  • 5 Department of Computer Science and Engineering, Texas A&M University, College Station, TX 77843, USA.
  • 6 Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX 77843, USA.
  • 7 Public Health Research Institute, New Jersey Medical School, Rutgers, State University of New Jersey, Newark, NJ 07103, USA. dis2003@med.cornell.edu dartoiva@njms.rutgers.edu.
  • 8 Department of Medicine, New Jersey Medical School, Rutgers, State University of New Jersey, Newark, NJ 07103, USA.
  • 9 Department of Microbiology and Immunology, Weill Cornell Medical College, New York, NY 10021, USA. dis2003@med.cornell.edu dartoiva@njms.rutgers.edu.
PMID: 29695454 DOI: 10.1126/scitranslmed.aal1803
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.

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