Targeting protein biotinylation enhances tuberculosis chemotherapy.

TitleTargeting protein biotinylation enhances tuberculosis chemotherapy.
Publication TypeJournal Article
Year of Publication2018
AuthorsTiwari D, Park SWoong, Essawy MM, Dawadi S, Mason A, Nandakumar M, Zimmerman M, Mina M, Ho HPin, Engelhart CA, Ioerger T, Sacchettini JC, Rhee K, Ehrt S, Aldrich CC, Dartois V, Schnappinger D
JournalSci Transl Med
Date Published2018 04 25
KeywordsAnimals, Antitubercular Agents, Bacterial Proteins, Biotinylation, Female, Mice, Mice, Inbred C57BL, Mycobacterium tuberculosis, Sulfurtransferases, Tuberculosis

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 .

Alternate JournalSci Transl Med
PubMed ID29695454
PubMed Central IDPMC6151865
Grant ListR01 AI091790 / AI / NIAID NIH HHS / United States
U19 AI111143 / AI / NIAID NIH HHS / United States

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