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Quinoline Derivatives Kill Mycobacterium tuberculosis by Activating Glutamate Kinase
Chinese Acad Sci, State Key Lab Resp Dis, Guangzhou Inst Biomed & Hlth, 190 Kaiyuan Ave,Sci Pk, Guangzhou 510530, Guangdong, Peoples R China.;Guangzhou Regenerat Med & Hlth Guangdong Lab GRM, 190 Kaiyuan Ave,Sci Pk, Guangzhou 510530, Guangdong, Peoples R China.;Univ Chinese Acad Sci, 19 Yuquan Rd, Beijing 100049, Peoples R China..
Chinese Acad Sci, State Key Lab Resp Dis, Guangzhou Inst Biomed & Hlth, 190 Kaiyuan Ave,Sci Pk, Guangzhou 510530, Guangdong, Peoples R China.;Chinese Acad Sci, Guangdong Prov Key Lab Biocomp, Guangzhou Inst Biomed & Hlth, 190 Kaiyuan Ave,Sci Pk, Guangzhou 510530, Guangdong, Peoples R China.;Univ Chinese Acad Sci, 19 Yuquan Rd, Beijing 100049, Peoples R China..
Chinese Acad Sci, State Key Lab Resp Dis, Guangzhou Inst Biomed & Hlth, 190 Kaiyuan Ave,Sci Pk, Guangzhou 510530, Guangdong, Peoples R China.;Guangzhou Regenerat Med & Hlth Guangdong Lab GRM, 190 Kaiyuan Ave,Sci Pk, Guangzhou 510530, Guangdong, Peoples R China.;Univ Chinese Acad Sci, 19 Yuquan Rd, Beijing 100049, Peoples R China..
Guangzhou Chest Hosp, Dept Clin Lab, State Key Lab Resp Dis, 62 Hengzhigang Rd, Guangzhou 510095, Guangdong, Peoples R China..
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2019 (English)In: Cell Chemical Biology, ISSN 2451-9456, E-ISSN 2451-9448, Vol. 26, no 8, p. 1187-+Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
CELL PRESS , 2019. Vol. 26, no 8, p. 1187-+
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Theoretical Chemistry
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URN: urn:nbn:se:kth:diva-257805DOI: 10.1016/j.chembiol.2019.05.003ISI: 000481604100015PubMedID: 31204286Scopus ID: 2-s2.0-85070354857OAI: oai:DiVA.org:kth-257805DiVA, id: diva2:1350853
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QC 20190912

Available from: 2019-09-12 Created: 2019-09-12 Last updated: 2019-09-12Bibliographically approved

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Zhou, Yang

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