Auxotrophy-based High Throughput Screening assay for the identification of Bacillus subtilis stringent response inhibitors
Andresen, Liis ; Varik, Vallo ; Tozawa, Yuzuru ; Jimmy, Steffi ; Lindberg, Stina ; Tenson, Tanel and Hauryliuk, Vasili LU
(2016)
In Scientific Reports
6.
- Abstract
The stringent response is a central adaptation mechanism that allows bacteria to adjust their growth and metabolism according to environmental conditions. The functionality of the stringent response is crucial for bacterial virulence, survival during host invasion as well as antibiotic resistance and tolerance. Therefore, specific inhibitors of the stringent response hold great promise as molecular tools for disarming and pacifying bacterial pathogens. By taking advantage of the valine amino acid auxotrophy of the Bacillus subtilis stringent response-deficient strain, we have set up a High Throughput Screening assay for the identification of stringent response inhibitors. By screening 17,500 compounds, we have identified a novel class... (More)
The stringent response is a central adaptation mechanism that allows bacteria to adjust their growth and metabolism according to environmental conditions. The functionality of the stringent response is crucial for bacterial virulence, survival during host invasion as well as antibiotic resistance and tolerance. Therefore, specific inhibitors of the stringent response hold great promise as molecular tools for disarming and pacifying bacterial pathogens. By taking advantage of the valine amino acid auxotrophy of the Bacillus subtilis stringent response-deficient strain, we have set up a High Throughput Screening assay for the identification of stringent response inhibitors. By screening 17,500 compounds, we have identified a novel class of antibacterials based on the 4-(6-(phenoxy)alkyl)-3,5-dimethyl-1H-pyrazole core. Detailed characterization of the hit compounds as well as two previously identified promising stringent response inhibitors - a ppGpp-mimic nucleotide Relacin and cationic peptide 1018 - showed that neither of the compounds is sufficiently specific, thus motivating future application of our screening assay to larger and more diverse molecular libraries.
(Less)
- author
- Andresen, Liis
; Varik, Vallo
; Tozawa, Yuzuru
; Jimmy, Steffi
; Lindberg, Stina
; Tenson, Tanel
and Hauryliuk, Vasili
LU
- publishing date
- 2016-10-24
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Scientific Reports
- volume
- 6
- article number
- 35824
- publisher
- Nature Publishing Group
- external identifiers
-
- pmid:27775002
- scopus:84992393626
- ISSN
- 2045-2322
- DOI
- 10.1038/srep35824
- language
- English
- LU publication?
- no
- additional info
- Funding Information: We are grateful to Per-Anders Enquist from Laboratories for Chemical Biology Ume? for helpful discussions and Dominik Rejman for synthesizing Relacin. This work was supported by the by grant IUT2-22 from the Estonian Research Council (TT); European Regional Development Fund through the Centre of Excellence for Molecular Cell Engineering (VH and TT); Estonian Science Foundation (PUT37 to VH); Ume? University, the Swedish Research council Vetenskapsr?det (grant 2013-4680), Kempe and Ragnar S?derberg foundations (VH). Publisher Copyright: © The Author(s) 2016. Copyright: Copyright 2016 Elsevier B.V., All rights reserved.
- id
- c8ce096c-78de-4df1-b84e-2e215e19885a
- date added to LUP
- 2021-09-24 20:42:47
- date last changed
- 2024-06-01 16:53:53
@article{c8ce096c-78de-4df1-b84e-2e215e19885a,
abstract = {{<p>The stringent response is a central adaptation mechanism that allows bacteria to adjust their growth and metabolism according to environmental conditions. The functionality of the stringent response is crucial for bacterial virulence, survival during host invasion as well as antibiotic resistance and tolerance. Therefore, specific inhibitors of the stringent response hold great promise as molecular tools for disarming and pacifying bacterial pathogens. By taking advantage of the valine amino acid auxotrophy of the Bacillus subtilis stringent response-deficient strain, we have set up a High Throughput Screening assay for the identification of stringent response inhibitors. By screening 17,500 compounds, we have identified a novel class of antibacterials based on the 4-(6-(phenoxy)alkyl)-3,5-dimethyl-1H-pyrazole core. Detailed characterization of the hit compounds as well as two previously identified promising stringent response inhibitors - a ppGpp-mimic nucleotide Relacin and cationic peptide 1018 - showed that neither of the compounds is sufficiently specific, thus motivating future application of our screening assay to larger and more diverse molecular libraries.</p>}},
author = {{Andresen, Liis and Varik, Vallo and Tozawa, Yuzuru and Jimmy, Steffi and Lindberg, Stina and Tenson, Tanel and Hauryliuk, Vasili}},
issn = {{2045-2322}},
language = {{eng}},
month = {{10}},
publisher = {{Nature Publishing Group}},
series = {{Scientific Reports}},
title = {{Auxotrophy-based High Throughput Screening assay for the identification of Bacillus subtilis stringent response inhibitors}},
url = {{http://dx.doi.org/10.1038/srep35824}},
doi = {{10.1038/srep35824}},
volume = {{6}},
year = {{2016}},
}