Binding and Action of Amino Acid Analogs of Chloramphenicol upon the Bacterial Ribosome

Andrey G. Tereshchenkov, Malgorzata Dobosz-Bartoszek, Ilya A. Osterman, James Marks, Vasilina A. Sergeeva, Pavel Kasatsky, Ekaterina S. Komarova, Andrey N. Stavrianidi, Igor A. Rodin, Andrey L. Konevega, Petr V. Sergiev, Natalia V. Sumbatyan, Alexander S. Mankin, Alexey A. Bogdanov, Yury S. Polikanov

    Research output: Contribution to journalArticlepeer-review

    29 Citations (Scopus)

    Abstract

    Antibiotic chloramphenicol (CHL) binds with a moderate affinity at the peptidyl transferase center of the bacterial ribosome and inhibits peptide bond formation. As an approach for modifying and potentially improving properties of this inhibitor, we explored ribosome binding and inhibitory activity of a number of amino acid analogs of CHL. The L-histidyl analog binds to the ribosome with the affinity exceeding that of CHL by 10 fold. Several of the newly synthesized analogs were able to inhibit protein synthesis and exhibited the mode of action that was distinct from the action of CHL. However, the inhibitory properties of the semi-synthetic CHL analogs did not correlate with their affinity and in general, the amino acid analogs of CHL were less active inhibitors of translation in comparison with the original antibiotic. The X-ray crystal structures of the Thermus thermophilus 70S ribosome in complex with three semi-synthetic analogs showed that CHL derivatives bind at the peptidyl transferase center, where the aminoacyl moiety of the tested compounds established idiosyncratic interactions with rRNA. Although still fairly inefficient inhibitors of translation, the synthesized compounds represent promising chemical scaffolds that target the peptidyl transferase center of the ribosome and potentially are suitable for further exploration.

    Original languageEnglish
    Pages (from-to)842-852
    Number of pages11
    JournalJournal of Molecular Biology
    Volume430
    Issue number6
    DOIs
    Publication statusPublished - 16 Mar 2018

    Keywords

    • antibiotic
    • peptidyl transferase center
    • protein synthesis
    • ribosome
    • X-ray structure

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