Targeting protein biotinylation enhances tuberculosis chemotherapy.

Journal:
Science translational medicine, Volume: 10, Issue: 438
Published:
April 25, 2018
PMID:
29695454
Authors:
Divya Tiwari D, Sae Woong Park SW, Maram M Essawy MM, Surendra Dawadi S, Alan Mason A, Madhumitha Nandakumar M, Matthew Zimmerman M, Marizel Mina M, Hsin Pin Ho HP, Curtis A Engelhart CA, Thomas Ioerger T, James C Sacchettini JC, Kyu Rhee K, Sabine Ehrt S, Courtney C Aldrich CC, VĂ©ronique Dartois V, Dirk Schnappinger D
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′-[-(d-biotinoyl)sulfamoyl]amino-5′-deoxyadenosine) killed (), 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 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 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 .