期刊
CELL CHEMICAL BIOLOGY
卷 26, 期 8, 页码 1187-+出版社
CELL PRESS
DOI: 10.1016/j.chembiol.2019.05.003
关键词
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资金
- Chinese Academy of Sciences [154144KYSB20150045, YJKYYQ20170036]
- Special Funds for Economic Development of Marine Economy of Guangdong Province [GDME-2018C003]
- State Key Laboratory of Respiratory Disease [SKLRD2016ZJ003, SKLRD-OP-201919]
- Science and Technology Innovation Leader of Guangdong Province [2016TX03R095]
- CAS-TWAS President's Fellowship for International PhD students
- CAS-PIFI
- Guangzhou Development Zone
There is a great need for identification and development of new anti-tuberculosis drugs with novel targets. Recent drug-discovery efforts typically focus on identifying inhibitors but not activators that perturb metabolic enzymes' functions as a means to kill Mycobacterium tuberculosis (Mtb). Here, we describe a class of quinoline compounds, Z0933/Z0930, which kill Mtb by acting as activators of glutamate kinase (GK), a previously untargeted enzyme catalyzing the first step of proline biosynthesis. We further show that Z0933/Z0930 augment proline production and induce Mtb killing via proline-derived redox imbalance and production of reactive oxygen species. This work highlights the effectiveness of gain-of-function probes against Mtb and provides a framework for the discovery of next-generation allosteric activators of GK.
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