IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v14y2023i1d10.1038_s41467-023-36528-7.html
   My bibliography  Save this article

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
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-023-36528-7
    File Function: Abstract
    Download Restriction: no

    File URL: https://libkey.io/10.1038/s41467-023-36528-7?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. 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.
    2. 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.
    3. 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.
    4. 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.
    5. 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.
    6. 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.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Dylan Girodat & Hans-Joachim Wieden & Scott C. Blanchard & Karissa Y. Sanbonmatsu, 2023. "Geometric alignment of aminoacyl-tRNA relative to catalytic centers of the ribosome underpins accurate mRNA decoding," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    2. Timo Flügel & Magdalena Schacherl & Anett Unbehaun & Birgit Schroeer & Marylena Dabrowski & Jörg Bürger & Thorsten Mielke & Thiemo Sprink & Christoph A. Diebolder & Yollete V. Guillén Schlippe & Chris, 2024. "Transient disome complex formation in native polysomes during ongoing protein synthesis captured by cryo-EM," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    3. Franziska Nadler & Elena Lavdovskaia & Angelique Krempler & Luis Daniel Cruz-Zaragoza & Sven Dennerlein & Ricarda Richter-Dennerlein, 2022. "Human mtRF1 terminates COX1 translation and its ablation induces mitochondrial ribosome-associated quality control," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    4. Jin Feng & Youle Zheng & Wanqing Ma & Defeng Weng & Dapeng Peng & Yindi Xu & Zhifang Wang & Xu Wang, 2024. "A synthetic antibiotic class with a deeply-optimized design for overcoming bacterial resistance," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    5. Sakshi Jain & Lukasz Koziej & Panagiotis Poulis & Igor Kaczmarczyk & Monika Gaik & Michal Rawski & Namit Ranjan & Sebastian Glatt & Marina V. Rodnina, 2023. "Modulation of translational decoding by m6A modification of mRNA," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    6. Lars V. Bock & Helmut Grubmüller, 2022. "Effects of cryo-EM cooling on structural ensembles," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    7. Valentyn Petrychenko & Bee-Zen Peng & Ana C. A. P. Schwarzer & Frank Peske & Marina V. Rodnina & Niels Fischer, 2021. "Structural mechanism of GTPase-powered ribosome-tRNA movement," Nature Communications, Nature, vol. 12(1), pages 1-9, December.
    8. Christine E. Carbone & Anna B. Loveland & Howard B. Gamper & Ya-Ming Hou & Gabriel Demo & Andrei A. Korostelev, 2021. "Time-resolved cryo-EM visualizes ribosomal translocation with EF-G and GTP," Nature Communications, Nature, vol. 12(1), pages 1-13, December.
    9. Chih-Wei Chen & Nadja Leimer & Egor A. Syroegin & Clémence Dunand & Zackery P. Bulman & Kim Lewis & Yury S. Polikanov & Maxim S. Svetlov, 2023. "Structural insights into the mechanism of overcoming Erm-mediated resistance by macrolides acting together with hygromycin-A," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    10. Xueqin Shu & Yingying Shi & Yi Huang & Dan Yu & Baolin Sun, 2023. "Transcription tuned by S-nitrosylation underlies a mechanism for Staphylococcus aureus to circumvent vancomycin killing," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    11. Tianyu Wu & Min Zhou & Jingcheng Zou & Qi Chen & Feng Qian & Jürgen Kurths & Runhui Liu & Yang Tang, 2024. "AI-guided few-shot inverse design of HDP-mimicking polymers against drug-resistant bacteria," Nature Communications, Nature, vol. 15(1), pages 1-22, December.
    12. Savannah M. Seely & Narayan P. Parajuli & Arindam Tarafder & Xueliang Ge & Suparna Sanyal & Matthieu G. Gagnon, 2023. "Molecular basis of the pleiotropic effects by the antibiotic amikacin on the ribosome," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    13. Panagiotis Poulis & Anoshi Patel & Marina V. Rodnina & Sarah Adio, 2022. "Altered tRNA dynamics during translocation on slippery mRNA as determinant of spontaneous ribosome frameshifting," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    14. Simon A. Fromm & Kate M. O’Connor & Michael Purdy & Pramod R. Bhatt & Gary Loughran & John F. Atkins & Ahmad Jomaa & Simone Mattei, 2023. "The translating bacterial ribosome at 1.55 Å resolution generated by cryo-EM imaging services," Nature Communications, Nature, vol. 14(1), pages 1-9, December.
    15. Jiekai Sun & Xu Wang & Ye Gao & Shuangyu Li & Ziwei Hu & Yan Huang & Baoqiang Fan & Xia Wang & Miao Liu & Chunhua Qiao & Wei Zhang & Yipeng Wang & Xingyue Ji, 2024. "H2S scavenger as a broad-spectrum strategy to deplete bacteria-derived H2S for antibacterial sensitization," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    16. Chencheng Qin & Yi Yang & Xiaodong Wu & Long Chen & Zhaoli Liu & Lin Tang & Lai Lyu & Danlian Huang & Dongbo Wang & Chang Zhang & Xingzhong Yuan & Wen Liu & Hou Wang, 2023. "Twistedly hydrophobic basis with suitable aromatic metrics in covalent organic networks govern micropollutant decontamination," Nature Communications, Nature, vol. 14(1), pages 1-11, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-36528-7. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.