In:
Science Translational Medicine, American Association for the Advancement of Science (AAAS), Vol. 10, No. 438 ( 2018-04-25)
Kurzfassung:
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 .
Materialart:
Online-Ressource
ISSN:
1946-6234
,
1946-6242
DOI:
10.1126/scitranslmed.aal1803
Sprache:
Englisch
Verlag:
American Association for the Advancement of Science (AAAS)
Publikationsdatum:
2018