Klebsazolicin inhibits 70S ribosome by obstructing the peptide exit tunnel

doi:10.1038/nchembio.2462

Title: Klebsazolicin inhibits 70S ribosome by obstructing the peptide exit tunnel

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Abstract

Whereas screening of the small-molecule metabolites produced by most cultivatable microorganisms often results in the rediscovery of known compounds, genome-mining programs allow researchers to harness much greater chemical diversity, and result in the discovery of new molecular scaffolds. Here we report the genome-guided identification of a new antibiotic, klebsazolicin (KLB), from Klebsiella pneumoniae that inhibits the growth of sensitive cells by targeting ribosomes. A ribosomally synthesized post-translationally modified peptide (RiPP), KLB is characterized by the presence of a unique N-terminal amidine ring that is essential for its activity. Biochemical in vitro studies indicate that KLB inhibits ribosomes by interfering with translation elongation. Structural analysis of the ribosome–KLB complex showed that the compound binds in the peptide exit tunnel overlapping with the binding sites of macrolides or streptogramin-B. KLB adopts a compact conformation and largely obstructs the tunnel. Engineered KLB fragments were observed to retain in vitro activity, and thus have the potential to serve as a starting point for the development of new bioactive compounds.

Authors:

; Osterman, Ilya A.; Ghilarov, Dmitry; Khabibullina, Nelli F.; Yakimov, Alexander; Shabalin, Konstantin; Utkina, Irina; Travin, Dmitry Y.; Komarova, Ekaterina S.; Serebryakova, Marina; Artamonova, Tatyana; Khodorkovskii, Mikhail; Konevega, Andrey L.; Sergiev, Petr V.; Severinov, Konstantin;

Publication Date:: 2017-08-28

Research Org.:: Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Org.:: NIHFOREIGNSTATE OF ILLINOIS

OSTI Identifier:: 1409111

Resource Type:: Journal Article

Journal Name:: Nature Chemical Biology

Additional Journal Information:: Journal Volume: 13; Journal Issue: 10; Journal ID: ISSN 1552-4450

Publisher:: Nature Publishing Group

Country of Publication:: United States

Language:: ENGLISH

Subject:: 59 BASIC BIOLOGICAL SCIENCES

Citation Formats


                    Metelev, Mikhail, Osterman, Ilya A., Ghilarov, Dmitry, Khabibullina, Nelli F., Yakimov, Alexander, Shabalin, Konstantin, Utkina, Irina, Travin, Dmitry Y., Komarova, Ekaterina S., Serebryakova, Marina, Artamonova, Tatyana, Khodorkovskii, Mikhail, Konevega, Andrey L., Sergiev, Petr V., Severinov, Konstantin, and Polikanov, Yury S. Klebsazolicin inhibits 70S ribosome by obstructing the peptide exit tunnel.  United States: N. p., 2017. 
        Web.  doi:10.1038/nchembio.2462.

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                    Metelev, Mikhail, Osterman, Ilya A., Ghilarov, Dmitry, Khabibullina, Nelli F., Yakimov, Alexander, Shabalin, Konstantin, Utkina, Irina, Travin, Dmitry Y., Komarova, Ekaterina S., Serebryakova, Marina, Artamonova, Tatyana, Khodorkovskii, Mikhail, Konevega, Andrey L., Sergiev, Petr V., Severinov, Konstantin, & Polikanov, Yury S. Klebsazolicin inhibits 70S ribosome by obstructing the peptide exit tunnel.  United States.  doi:10.1038/nchembio.2462.

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                    Metelev, Mikhail, Osterman, Ilya A., Ghilarov, Dmitry, Khabibullina, Nelli F., Yakimov, Alexander, Shabalin, Konstantin, Utkina, Irina, Travin, Dmitry Y., Komarova, Ekaterina S., Serebryakova, Marina, Artamonova, Tatyana, Khodorkovskii, Mikhail, Konevega, Andrey L., Sergiev, Petr V., Severinov, Konstantin, and Polikanov, Yury S. Mon .  
        "Klebsazolicin inhibits 70S ribosome by obstructing the peptide exit tunnel".  United States.  doi:10.1038/nchembio.2462.

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@article{osti_1409111,

  title        = {Klebsazolicin inhibits 70S ribosome by obstructing the peptide exit tunnel},

  author       = {Metelev, Mikhail and Osterman, Ilya A. and Ghilarov, Dmitry and Khabibullina, Nelli F. and Yakimov, Alexander and Shabalin, Konstantin and Utkina, Irina and Travin, Dmitry Y. and Komarova, Ekaterina S. and Serebryakova, Marina and Artamonova, Tatyana and Khodorkovskii, Mikhail and Konevega, Andrey L. and Sergiev, Petr V. and Severinov, Konstantin and Polikanov, Yury S.},

  abstractNote = {Whereas screening of the small-molecule metabolites produced by most cultivatable microorganisms often results in the rediscovery of known compounds, genome-mining programs allow researchers to harness much greater chemical diversity, and result in the discovery of new molecular scaffolds. Here we report the genome-guided identification of a new antibiotic, klebsazolicin (KLB), from Klebsiella pneumoniae that inhibits the growth of sensitive cells by targeting ribosomes. A ribosomally synthesized post-translationally modified peptide (RiPP), KLB is characterized by the presence of a unique N-terminal amidine ring that is essential for its activity. Biochemical in vitro studies indicate that KLB inhibits ribosomes by interfering with translation elongation. Structural analysis of the ribosome–KLB complex showed that the compound binds in the peptide exit tunnel overlapping with the binding sites of macrolides or streptogramin-B. KLB adopts a compact conformation and largely obstructs the tunnel. Engineered KLB fragments were observed to retain in vitro activity, and thus have the potential to serve as a starting point for the development of new bioactive compounds.},

  doi          = {10.1038/nchembio.2462},

  journal      = {Nature Chemical Biology},

  issn         = {1552-4450},

  number       = 10,

  volume       = 13,

  place        = {United States},

  year         = {2017},

  month        = {8}

}

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DOI: 10.1038/nchembio.2462

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