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Antibiotic thermorubin tethers ribosomal subunits and impedes A-site interactions to perturb protein synthesis in bacteria

Author

Listed:
  • Narayan Prasad Parajuli

    (Uppsala University)

  • Andrew Emmerich

    (Uppsala University)

  • Chandra Sekhar Mandava

    (Uppsala University)

  • Michael Y. Pavlov

    (Uppsala University)

  • Suparna Sanyal

    (Uppsala University)

Abstract

Thermorubin (THB) is a long-known broad-spectrum ribosome-targeting antibiotic, but the molecular mechanism of its action was unclear. Here, our precise fast-kinetics assays in a reconstituted Escherichia coli translation system and 1.96 Å resolution cryo-EM structure of THB-bound 70S ribosome with mRNA and initiator tRNA, independently suggest that THB binding at the intersubunit bridge B2a near decoding center of the ribosome interferes with the binding of A-site substrates aminoacyl-tRNAs and class-I release factors, thereby inhibiting elongation and termination steps of bacterial translation. Furthermore, THB acts as an anti-dissociation agent that tethers the ribosomal subunits and blocks ribosome recycling, subsequently reducing the pool of active ribosomes. Our results show that THB does not inhibit translation initiation as proposed earlier and provide a complete mechanism of how THB perturbs bacterial protein synthesis. This in-depth characterization will hopefully spur efforts toward the design of THB analogs with improved solubility and effectivity against multidrug-resistant bacteria.

Suggested Citation

  • Narayan Prasad Parajuli & Andrew Emmerich & Chandra Sekhar Mandava & Michael Y. Pavlov & Suparna Sanyal, 2023. "Antibiotic thermorubin tethers ribosomal subunits and impedes A-site interactions to perturb protein synthesis in bacteria," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-36528-7
    DOI: 10.1038/s41467-023-36528-7
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    1. Matthew J. Mitcheltree & Amarnath Pisipati & Egor A. Syroegin & Katherine J. Silvestre & Dorota Klepacki & Jeremy D. Mason & Daniel W. Terwilliger & Giambattista Testolin & Aditya R. Pote & Kelvin J. , 2021. "A synthetic antibiotic class overcoming bacterial multidrug resistance," Nature, Nature, vol. 599(7885), pages 507-512, November.
    2. Ritwika S. Basu & Michael B. Sherman & Matthieu G. Gagnon, 2022. "Compact IF2 allows initiator tRNA accommodation into the P site and gates the ribosome to elongation," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    3. Michael R. Wasserman & Arto Pulk & Zhou Zhou & Roger B. Altman & John C. Zinder & Keith D. Green & Sylvie Garneau-Tsodikova & Jamie H. Doudna Cate & Scott C. Blanchard, 2015. "Chemically related 4,5-linked aminoglycoside antibiotics drive subunit rotation in opposite directions," Nature Communications, Nature, vol. 6(1), pages 1-12, November.
    4. Ziao Fu & Gabriele Indrisiunaite & Sandip Kaledhonkar & Binita Shah & Ming Sun & Bo Chen & Robert A. Grassucci & Måns Ehrenberg & Joachim Frank, 2019. "The structural basis for release-factor activation during translation termination revealed by time-resolved cryogenic electron microscopy," Nature Communications, Nature, vol. 10(1), pages 1-7, December.
    5. Emily J. Rundlet & Mikael Holm & Magdalena Schacherl & S. Kundhavai Natchiar & Roger B. Altman & Christian M. T. Spahn & Alexander G. Myasnikov & Scott C. Blanchard, 2021. "Structural basis of early translocation events on the ribosome," Nature, Nature, vol. 595(7869), pages 741-745, July.
    6. Martin Laurberg & Haruichi Asahara & Andrei Korostelev & Jianyu Zhu & Sergei Trakhanov & Harry F. Noller, 2008. "Structural basis for translation termination on the 70S ribosome," Nature, Nature, vol. 454(7206), pages 852-857, August.
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