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Targeting protein biotinylation enhances tuberculosis chemotherapy
Science Translational Medicine ( IF 15.8 ) Pub Date : 2018-04-25 , DOI: 10.1126/scitranslmed.aal1803
Divya Tiwari 1 , Sae Woong Park 1 , Maram M. Essawy 2 , Surendra Dawadi 2 , Alan Mason 3 , Madhumitha Nandakumar 4 , Matthew Zimmerman 3 , Marizel Mina 3 , Hsin Pin Ho 3 , Curtis A. Engelhart 1 , Thomas Ioerger 5 , James C. Sacchettini 6 , Kyu Rhee 4 , Sabine Ehrt 1 , Courtney C. Aldrich 2 , Véronique Dartois 3, 7 , Dirk Schnappinger 1
Affiliation  

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.



中文翻译:

靶向蛋白质生物素化可增强结核病化疗

结核病(TB)的成功药物治疗取决于其组成药物的独特贡献。耐药性对单个药物的功效和它们所贡献的疗法构成了威胁。能够替代当前结核病化疗中各个成分的经过生物和化学验证的靶标是结核病药物开发中的主要未满足需求。我们证明化学抑制细菌生物素蛋白连接酶(BPL)与抑制剂Bio-AMS(5'-[ N-d-生物素酰基)氨磺酰基]氨基-5'-脱氧腺苷)杀死了结核分枝杆菌Mtb),引起结核病的细菌病原体。我们还表明,在急性和慢性Mtb感染期间,BPL的基因沉默有效地消除了小鼠的病原体。BPL的部分化学失活增加了两种一线药物利福平和乙胺丁醇的效力,并且对蛋白质生物素化的遗传干扰加速了利福平从小鼠肺和脾中清除Mtb。这些研究证实BPL是潜在的药物靶标,可以作为开发抗Mtb的新药物的替代性一线靶标。

更新日期:2018-04-26
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