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

J. Beljantseva, P. Kudrin, S. Jimmy, M. Ehn, R. Pohl, V. Varik, Y. Tozawa, V. Shingler, T. Tenson, D. Rejman, V. Hauryliuk,

. 2017 ; 7 (-) : 41839. [pub] 20170203

Language English Country England, Great Britain

Document type Journal Article, Research Support, Non-U.S. Gov't

Persistent link   https://www.medvik.cz/link/bmc19001324

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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$a Beljantseva, Jelena $u University of Tartu, Institute of Technology, Nooruse 1, 50411 Tartu, Estonia.
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$a 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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$a Kudrin, Pavel $u University of Tartu, Institute of Technology, Nooruse 1, 50411 Tartu, Estonia.
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$a Jimmy, Steffi $u Department of Molecular Biology, Umeå University, Building 6K, 6L University Hospital Area, SE-901 87 Umeå, Sweden. Laboratory for Molecular Infection Medicine Sweden (MIMS), Umeå University, Building 6K and 6L, University Hospital Area, SE-901 87 Umeå, Sweden.
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$a Ehn, Marcel $u Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences v.v.i., Flemingovo nám. 2, 166 10 Prague 6, Czech Republic.
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$a Pohl, Radek $u Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences v.v.i., Flemingovo nám. 2, 166 10 Prague 6, Czech Republic.
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$a Varik, Vallo $u University of Tartu, Institute of Technology, Nooruse 1, 50411 Tartu, Estonia. Department of Molecular Biology, Umeå University, Building 6K, 6L University Hospital Area, SE-901 87 Umeå, Sweden. Laboratory for Molecular Infection Medicine Sweden (MIMS), Umeå University, Building 6K and 6L, University Hospital Area, SE-901 87 Umeå, Sweden.
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$a Tozawa, Yuzuru $u Graduate School of Science and Engineering, Saitama University, 255 Shimo-Okubo, Sakura-ku, Saitama, Saitama 338-8570, Japan.
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$a Shingler, Victoria $u Department of Molecular Biology, Umeå University, Building 6K, 6L University Hospital Area, SE-901 87 Umeå, Sweden.
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$a Tenson, Tanel $u University of Tartu, Institute of Technology, Nooruse 1, 50411 Tartu, Estonia.
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$a Rejman, Dominik $u Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences v.v.i., Flemingovo nám. 2, 166 10 Prague 6, Czech Republic.
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$a Hauryliuk, Vasili $u University of Tartu, Institute of Technology, Nooruse 1, 50411 Tartu, Estonia. Department of Molecular Biology, Umeå University, Building 6K, 6L University Hospital Area, SE-901 87 Umeå, Sweden. Laboratory for Molecular Infection Medicine Sweden (MIMS), Umeå University, Building 6K and 6L, University Hospital Area, SE-901 87 Umeå, Sweden.
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