IDEAS home Printed from https://ideas.repec.org/a/plo/pcbi00/1003113.html
   My bibliography  Save this article

Impact of Ribosomal Modification on the Binding of the Antibiotic Telithromycin Using a Combined Grand Canonical Monte Carlo/Molecular Dynamics Simulation Approach

Author

Listed:
  • Meagan C Small
  • Pedro Lopes
  • Rodrigo B Andrade
  • Alexander D MacKerell Jr

Abstract

Resistance to macrolide antibiotics is conferred by mutation of A2058 to G or methylation by Erm methyltransferases of the exocyclic N6 of A2058 (E. coli numbering) that forms the macrolide binding site in the 50S subunit of the ribosome. Ketolides such as telithromycin mitigate A2058G resistance yet remain susceptible to Erm-based resistance. Molecular details associated with macrolide resistance due to the A2058G mutation and methylation at N6 of A2058 by Erm methyltransferases were investigated using empirical force field-based simulations. To address the buried nature of the macrolide binding site, the number of waters within the pocket was allowed to fluctuate via the use of a Grand Canonical Monte Carlo (GCMC) methodology. The GCMC water insertion/deletion steps were alternated with Molecular Dynamics (MD) simulations to allow for relaxation of the entire system. From this GCMC/MD approach information on the interactions between telithromycin and the 50S ribosome was obtained. In the wild-type (WT) ribosome, the 2′-OH to A2058 N1 hydrogen bond samples short distances with a higher probability, while the effectiveness of telithromycin against the A2058G mutation is explained by a rearrangement of the hydrogen bonding pattern of the 2′-OH to 2058 that maintains the overall antibiotic-ribosome interactions. In both the WT and A2058G mutation there is significant flexibility in telithromycin's imidazole-pyridine side chain (ARM), indicating that entropic effects contribute to the binding affinity. Methylated ribosomes show lower sampling of short 2′-OH to 2058 distances and also demonstrate enhanced G2057-A2058 stacking leading to disrupted A752-U2609 Watson-Crick (WC) interactions as well as hydrogen bonding between telithromycin's ARM and U2609. This information will be of utility in the rational design of novel macrolide analogs with improved activity against methylated A2058 ribosomes.Author Summary: Bacterial resistance to antibiotics is a serious public health problem that requires the continuous development of new antibiotics. Bacteria acquire resistance to macrolide antibiotics by (1) effluxing the drug from the cell, (2) modifying the drug, or (3) modifying the drug target (i.e., the 50S subunit of the ribosome) to abrogate or completely abolish binding. While newer antibiotics are able to avoid the first two mechanisms, they remain unable to overcome resistance due to ribosomal modification, particularly due to methyltransferase (i.e., erm) enzymes. We have applied computer-aided drug design methods designed explicitly for studies of the ribosome to better understand the relationship between modification of the ribosome by erms and the binding of telithromycin, a 3rd generation ketolide antibiotic derived from erythromycin. While we confirm that ribosomal modification leads to decreased binding due to disruption of key interactions with the drug, we find these modifications effect a structural rearrangement of the entire region of the ribosome responsible for binding macrolide antibiotics. This information will be useful in the design of novel antibiotics that are effective against resistant bacteria possessing modified ribosomes.

Suggested Citation

  • Meagan C Small & Pedro Lopes & Rodrigo B Andrade & Alexander D MacKerell Jr, 2013. "Impact of Ribosomal Modification on the Binding of the Antibiotic Telithromycin Using a Combined Grand Canonical Monte Carlo/Molecular Dynamics Simulation Approach," PLOS Computational Biology, Public Library of Science, vol. 9(6), pages 1-14, June.
  • Handle: RePEc:plo:pcbi00:1003113
    DOI: 10.1371/journal.pcbi.1003113
    as

    Download full text from publisher

    File URL: https://journals.plos.org/ploscompbiol/article?id=10.1371/journal.pcbi.1003113
    Download Restriction: no

    File URL: https://journals.plos.org/ploscompbiol/article/file?id=10.1371/journal.pcbi.1003113&type=printable
    Download Restriction: no

    File URL: https://libkey.io/10.1371/journal.pcbi.1003113?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. Andrew P. Carter & William M. Clemons & Ditlev E. Brodersen & Robert J. Morgan-Warren & Brian T. Wimberly & V. Ramakrishnan, 2000. "Functional insights from the structure of the 30S ribosomal subunit and its interactions with antibiotics," Nature, Nature, vol. 407(6802), pages 340-348, September.
    2. Brian T. Wimberly & Ditlev E. Brodersen & William M. Clemons & Robert J. Morgan-Warren & Andrew P. Carter & Clemens Vonrhein & Thomas Hartsch & V. Ramakrishnan, 2000. "Structure of the 30S ribosomal subunit," Nature, Nature, vol. 407(6802), pages 327-339, September.
    3. Frank Schlünzen & Raz Zarivach & Jörg Harms & Anat Bashan & Ante Tocilj & Renate Albrecht & Ada Yonath & François Franceschi, 2001. "Structural basis for the interaction of antibiotics with the peptidyl transferase centre in eubacteria," Nature, Nature, vol. 413(6858), pages 814-821, October.
    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. Rebecca S Mathew-Fenn & Rhiju Das & Joshua A Silverman & Peter A Walker & Pehr A B Harbury, 2008. "A Molecular Ruler for Measuring Quantitative Distance Distributions," PLOS ONE, Public Library of Science, vol. 3(10), pages 1-9, October.
    2. Noriyuki Uchida & Ai Kohata & Kou Okuro & Annalisa Cardellini & Chiara Lionello & Eric A. Zizzi & Marco A. Deriu & Giovanni M. Pavan & Michio Tomishige & Takaaki Hikima & Takuzo Aida, 2022. "Reconstitution of microtubule into GTP-responsive nanocapsules," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    3. 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.
    4. Mariam Jaafar & Julia Contreras & Carine Dominique & Sara Martín-Villanueva & Régine Capeyrou & Patrice Vitali & Olga Rodríguez-Galán & Carmen Velasco & Odile Humbert & Nicholas J. Watkins & Eduardo V, 2021. "Association of snR190 snoRNA chaperone with early pre-60S particles is regulated by the RNA helicase Dbp7 in yeast," Nature Communications, Nature, vol. 12(1), pages 1-17, 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:plo:pcbi00:1003113. 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: ploscompbiol (email available below). General contact details of provider: https://journals.plos.org/ploscompbiol/ .

    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.