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- Makafe, Gaelle G., et al.
(författare)
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Quinoline Derivatives Kill Mycobacterium tuberculosis by Activating Glutamate Kinase
- 2019
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Ingår i: Cell Chemical Biology. - : CELL PRESS. - 2451-9456 .- 2451-9448. ; 26:8, s. 1187-
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Tidskriftsartikel (refereegranskat)abstract
- 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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