Profiling of in vitro activities of urea-based inhibitors against cysteine synthases from Mycobacterium tuberculosis
(2017) In Bioorganic and Medicinal Chemistry Letters 27(19). p.4582-4587- Abstract
CysK1 and CysK2 are two members of the cysteine/S-sulfocysteine synthase family in Mycobacterium tuberculosis, responsible for the de novo biosynthesis of L-cysteine, which is subsequently used as a building block for mycothiol. This metabolite is the first line defense of this pathogen against reactive oxygen and nitrogen species released by host macrophages after phagocytosis. In a previous medicinal chemistry campaign we had developed urea-based inhibitors of the cysteine synthase CysM with bactericidal activity against dormant M. tuberculosis. In this study we extended these efforts by examination of the in vitro activities of a library consisting of 71 urea compounds against CysK1 and CysK2. Binding was established by fluorescence... (More)
CysK1 and CysK2 are two members of the cysteine/S-sulfocysteine synthase family in Mycobacterium tuberculosis, responsible for the de novo biosynthesis of L-cysteine, which is subsequently used as a building block for mycothiol. This metabolite is the first line defense of this pathogen against reactive oxygen and nitrogen species released by host macrophages after phagocytosis. In a previous medicinal chemistry campaign we had developed urea-based inhibitors of the cysteine synthase CysM with bactericidal activity against dormant M. tuberculosis. In this study we extended these efforts by examination of the in vitro activities of a library consisting of 71 urea compounds against CysK1 and CysK2. Binding was established by fluorescence spectroscopy and inhibition by enzyme assays. Several of the compounds inhibited these two cysteine synthases, with the most potent inhibitor displaying an IC50 value of 2.5 µM for CysK1 and 6.6 µM for CysK2, respectively. Four of the identified molecules targeting CysK1 and CysK2 were also among the top ten inhibitors of CysM, suggesting that potent compounds could be developed with activity against all three enzymes.
(Less)
- author
- Brunner, Katharina
; Steiner, Eva Maria
LU
; Reshma, Rudraraju Srilakshmi ; Sriram, Dharmarajan ; Schnell, Robert and Schneider, Gunter
- publishing date
- 2017
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- Cysteine biosynthesis, Cysteine synthase, Inhibition, Mycobacterium tuberculosis
- in
- Bioorganic and Medicinal Chemistry Letters
- volume
- 27
- issue
- 19
- pages
- 4582 - 4587
- publisher
- Elsevier
- external identifiers
-
- pmid:28882483
- scopus:85028687384
- ISSN
- 0960-894X
- DOI
- 10.1016/j.bmcl.2017.08.039
- language
- English
- LU publication?
- no
- additional info
- Publisher Copyright: © 2017
- id
- 5eb8b40a-47e7-4dfe-85c8-924afe5f1fcd
- date added to LUP
- 2024-12-11 10:43:24
- date last changed
- 2025-04-04 14:47:13
@article{5eb8b40a-47e7-4dfe-85c8-924afe5f1fcd, abstract = {{<p>CysK1 and CysK2 are two members of the cysteine/S-sulfocysteine synthase family in Mycobacterium tuberculosis, responsible for the de novo biosynthesis of L-cysteine, which is subsequently used as a building block for mycothiol. This metabolite is the first line defense of this pathogen against reactive oxygen and nitrogen species released by host macrophages after phagocytosis. In a previous medicinal chemistry campaign we had developed urea-based inhibitors of the cysteine synthase CysM with bactericidal activity against dormant M. tuberculosis. In this study we extended these efforts by examination of the in vitro activities of a library consisting of 71 urea compounds against CysK1 and CysK2. Binding was established by fluorescence spectroscopy and inhibition by enzyme assays. Several of the compounds inhibited these two cysteine synthases, with the most potent inhibitor displaying an IC<sub>50</sub> value of 2.5 µM for CysK1 and 6.6 µM for CysK2, respectively. Four of the identified molecules targeting CysK1 and CysK2 were also among the top ten inhibitors of CysM, suggesting that potent compounds could be developed with activity against all three enzymes.</p>}}, author = {{Brunner, Katharina and Steiner, Eva Maria and Reshma, Rudraraju Srilakshmi and Sriram, Dharmarajan and Schnell, Robert and Schneider, Gunter}}, issn = {{0960-894X}}, keywords = {{Cysteine biosynthesis; Cysteine synthase; Inhibition; Mycobacterium tuberculosis}}, language = {{eng}}, number = {{19}}, pages = {{4582--4587}}, publisher = {{Elsevier}}, series = {{Bioorganic and Medicinal Chemistry Letters}}, title = {{Profiling of in vitro activities of urea-based inhibitors against cysteine synthases from Mycobacterium tuberculosis}}, url = {{http://dx.doi.org/10.1016/j.bmcl.2017.08.039}}, doi = {{10.1016/j.bmcl.2017.08.039}}, volume = {{27}}, year = {{2017}}, }