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Profiling of in vitro activities of urea-based inhibitors against cysteine synthases from Mycobacterium tuberculosis

Brunner, Katharina ; Steiner, Eva Maria LU orcid ; Reshma, Rudraraju Srilakshmi ; Sriram, Dharmarajan ; Schnell, Robert and Schneider, Gunter (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.

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author
; ; ; ; and
publishing date
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}},
}