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Molecular mutagenesis of ppGpp : Turning a RelA activator into an inhibitor

Beljantseva, Jelena ; Kudrin, Pavel ; Jimmy, Steffi ; Ehn, Marcel ; Pohl, Radek ; Varik, Vallo ; Tozawa, Yuzuru ; Shingler, Victoria ; Tenson, Tanel and Rejman, Dominik , et al. (2017) In Scientific Reports 7. p.1-10
Abstract

The alarmone nucleotide (p)ppGpp is a key regulator of bacterial metabolism, growth, stress tolerance and virulence, making (p)ppGpp-mediated signaling a promising target for development of antibacterials. Although ppGpp itself is an activator of the ribosome-associated ppGpp synthetase RelA, several ppGpp mimics have been developed as RelA inhibitors. However promising, the currently available ppGpp mimics are relatively inefficient, with IC50 in the sub-mM range. In an attempt to identify a potent and specific inhibitor of RelA capable of abrogating (p)ppGpp production in live bacterial cells, we have tested a targeted nucleotide library using a biochemical test system comprised of purified Escherichia coli components.... (More)

The alarmone nucleotide (p)ppGpp is a key regulator of bacterial metabolism, growth, stress tolerance and virulence, making (p)ppGpp-mediated signaling a promising target for development of antibacterials. Although ppGpp itself is an activator of the ribosome-associated ppGpp synthetase RelA, several ppGpp mimics have been developed as RelA inhibitors. However promising, the currently available ppGpp mimics are relatively inefficient, with IC50 in the sub-mM range. In an attempt to identify a potent and specific inhibitor of RelA capable of abrogating (p)ppGpp production in live bacterial cells, we have tested a targeted nucleotide library using a biochemical test system comprised of purified Escherichia coli components. While none of the compounds fulfilled this aim, the screen has yielded several potentially useful molecular tools for biochemical and structural work.

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publishing date
type
Contribution to journal
publication status
published
in
Scientific Reports
volume
7
article number
41839
pages
1 - 10
publisher
Nature Publishing Group
external identifiers
  • pmid:28157202
  • scopus:85011591064
ISSN
2045-2322
DOI
10.1038/srep41839
language
English
LU publication?
no
additional info
Funding Information: We are grateful to Liis Andresen for setting up the B. subtilis growth assays. This work was supported by the funds from European Regional Development Fund through the Centre of Excellence in Molecular Cell Engineering (VH and TT), Estonian Research Council grants (PUT37 to VH, IUT2.22 to TT); Umea. University, Swedish Research council (2013.4680 to VH and 2011-4791 to VS), Ragnar Soderberg and Kempe foundations (VH); Czech Science Foundation grant number 15-11711S (DR). Collaboration between VH, YT and DR labs was supported by grant 202100-2874 from the Swedish foundation for international cooperation in research and higher education (STINT). Publisher Copyright: © The Author(s) 2017. Copyright: Copyright 2018 Elsevier B.V., All rights reserved.
id
c36a86e8-779e-4937-bf17-42e235237098
date added to LUP
2021-09-24 20:40:32
date last changed
2025-04-20 22:14:02
@article{c36a86e8-779e-4937-bf17-42e235237098,
  abstract     = {{<p>The alarmone nucleotide (p)ppGpp is a key regulator of bacterial metabolism, growth, stress tolerance and virulence, making (p)ppGpp-mediated signaling a promising target for development of antibacterials. Although ppGpp itself is an activator of the ribosome-associated ppGpp synthetase RelA, several ppGpp mimics have been developed as RelA inhibitors. However promising, the currently available ppGpp mimics are relatively inefficient, with IC<sub>50</sub> in the sub-mM range. In an attempt to identify a potent and specific inhibitor of RelA capable of abrogating (p)ppGpp production in live bacterial cells, we have tested a targeted nucleotide library using a biochemical test system comprised of purified Escherichia coli components. While none of the compounds fulfilled this aim, the screen has yielded several potentially useful molecular tools for biochemical and structural work.</p>}},
  author       = {{Beljantseva, Jelena and Kudrin, Pavel and Jimmy, Steffi and Ehn, Marcel and Pohl, Radek and Varik, Vallo and Tozawa, Yuzuru and Shingler, Victoria and Tenson, Tanel and Rejman, Dominik and Hauryliuk, Vasili}},
  issn         = {{2045-2322}},
  language     = {{eng}},
  pages        = {{1--10}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Scientific Reports}},
  title        = {{Molecular mutagenesis of ppGpp : Turning a RelA activator into an inhibitor}},
  url          = {{http://dx.doi.org/10.1038/srep41839}},
  doi          = {{10.1038/srep41839}},
  volume       = {{7}},
  year         = {{2017}},
}