Klebsazolicin inhibits 70S ribosome by obstructing the peptide exit tunnel

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

    Research output: Contribution to journalArticlepeer-review

    30 Citations (Scopus)


    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.

    Original languageEnglish
    Pages (from-to)1129-1136
    Number of pages8
    JournalNature Chemical Biology
    Issue number10
    Publication statusPublished - 1 Oct 2017


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