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Auxotrophy-based High Throughput Screening assay for the identification of Bacillus subtilis stringent response inhibitors
Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). University of Tartu, Institute of Technology, Nooruse 1, 50411 Tartu, Estonia.
Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
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2016 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, 35824Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2016. Vol. 6, 35824
National Category
Microbiology Infectious Medicine
Identifiers
URN: urn:nbn:se:umu:diva-127600DOI: 10.1038/srep35824ISI: 000385923600001PubMedID: 27775002OAI: oai:DiVA.org:umu-127600DiVA: diva2:1052657
Available from: 2016-12-07 Created: 2016-11-16 Last updated: 2016-12-07Bibliographically approved

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Andresen, LiisVarik, ValloJimmy, SteffiLindberg, StinaHauryliuk, Vasili
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Department of Molecular Biology (Faculty of Medicine)Molecular Infection Medicine Sweden (MIMS)Department of Chemistry
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