TY - JOUR
T1 - Targeting protein biotinylation enhances tuberculosis chemotherapy
AU - Tiwari, Divya
AU - Park, Sae Woong
AU - Essawy, Maram M.
AU - Dawadi, Surendra
AU - Mason, Alan
AU - Nandakumar, Madhumitha
AU - Zimmerman, Matthew
AU - Mina, Marizel
AU - Ho, Hsin Pin
AU - Engelhart, Curtis A.
AU - Ioerger, Thomas
AU - Sacchettini, James C.
AU - Rhee, Kyu
AU - Ehrt, Sabine
AU - Aldrich, Courtney C.
AU - Dartois, Véronique
AU - Schnappinger, Dirk
N1 - Funding Information:
This work was supported by grant #AI091790 [National Institute of Allergy and Infectious Diseases (NIAID)] to D.S. and C.C.A., #U19AI111143 (Tri-Institutional TB Research Unit, part of the NIAID Tuberculosis Research Units Network) to D.S. and V.D., a chair from Welch foundation (A-0015) to J.C.S., and #OPP1154895 from the Bill and Melinda Gates Foundation to V.D. and D.S.
PY - 2018/4/25
Y1 - 2018/4/25
N2 - 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.
AB - 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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U2 - 10.1126/scitranslmed.aal1803
DO - 10.1126/scitranslmed.aal1803
M3 - Article
C2 - 29695454
AN - SCOPUS:85046358808
SN - 1946-6234
VL - 10
JO - Science Translational Medicine
JF - Science Translational Medicine
IS - 438
M1 - eaal1803
ER -
