Research ArticleTuberculosis

Targeting protein biotinylation enhances tuberculosis chemotherapy

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Science Translational Medicine  25 Apr 2018:
Vol. 10, Issue 438, eaal1803
DOI: 10.1126/scitranslmed.aal1803

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A new drug target for combatting TB

Mycobacterium tuberculosis (Mtb) is the causative agent of tuberculosis (TB). The paucity of validated drug targets limits efforts to develop new drugs to combat TB. New work by Tiwari et al. establishes bacterial biotin protein ligase (BPL), the enzyme Mtb requires to covalently attach the essential vitamin biotin to biotin-dependent enzymes, as an alternative frontline target in the development of drugs against TB. These investigators demonstrated that inactivation of BPL killed Mtb in vitro and eradicated this pathogen from infected mice. Inhibition of protein biotinylation increased the potency of the frontline TB drug rifampicin both in vitro and during infection of mice.

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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