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Structural basis of ABCF-mediated resistance to pleuromutilin, lincosamide, and streptogramin A antibiotics in Gram-positive pathogens

Author

Listed:
  • Caillan Crowe-McAuliffe

    (University of Hamburg)

  • Victoriia Murina

    (Umeå University
    Umeå University)

  • Kathryn Jane Turnbull

    (Umeå University
    Umeå University)

  • Marje Kasari

    (University of Tartu, Institute of Technology)

  • Merianne Mohamad

    (University of Leeds)

  • Christine Polte

    (University of Hamburg)

  • Hiraku Takada

    (Umeå University
    Umeå University)

  • Karolis Vaitkevicius

    (Umeå University
    Umeå University)

  • Jörgen Johansson

    (Umeå University
    Umeå University)

  • Zoya Ignatova

    (University of Hamburg)

  • Gemma C. Atkinson

    (Umeå University)

  • Alex J. O’Neill

    (University of Leeds)

  • Vasili Hauryliuk

    (Umeå University
    Umeå University
    University of Tartu, Institute of Technology
    Lund University)

  • Daniel N. Wilson

    (University of Hamburg)

Abstract

Target protection proteins confer resistance to the host organism by directly binding to the antibiotic target. One class of such proteins are the antibiotic resistance (ARE) ATP-binding cassette (ABC) proteins of the F-subtype (ARE-ABCFs), which are widely distributed throughout Gram-positive bacteria and bind the ribosome to alleviate translational inhibition from antibiotics that target the large ribosomal subunit. Here, we present single-particle cryo-EM structures of ARE-ABCF-ribosome complexes from three Gram-positive pathogens: Enterococcus faecalis LsaA, Staphylococcus haemolyticus VgaALC and Listeria monocytogenes VgaL. Supported by extensive mutagenesis analysis, these structures enable a general model for antibiotic resistance mediated by these ARE-ABCFs to be proposed. In this model, ABCF binding to the antibiotic-stalled ribosome mediates antibiotic release via mechanistically diverse long-range conformational relays that converge on a few conserved ribosomal RNA nucleotides located at the peptidyltransferase center. These insights are important for the future development of antibiotics that overcome such target protection resistance mechanisms.

Suggested Citation

  • Caillan Crowe-McAuliffe & Victoriia Murina & Kathryn Jane Turnbull & Marje Kasari & Merianne Mohamad & Christine Polte & Hiraku Takada & Karolis Vaitkevicius & Jörgen Johansson & Zoya Ignatova & Gemma, 2021. "Structural basis of ABCF-mediated resistance to pleuromutilin, lincosamide, and streptogramin A antibiotics in Gram-positive pathogens," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-23753-1
    DOI: 10.1038/s41467-021-23753-1
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    Cited by:

    1. Corentin R. Fostier & Farès Ousalem & Elodie C. Leroy & Saravuth Ngo & Heddy Soufari & C. Axel Innis & Yaser Hashem & Grégory Boël, 2023. "Regulation of the macrolide resistance ABC-F translation factor MsrD," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    2. Caillan Crowe-McAuliffe & Victoriia Murina & Kathryn Jane Turnbull & Susanne Huch & Marje Kasari & Hiraku Takada & Lilit Nersisyan & Arnfinn Sundsfjord & Kristin Hegstad & Gemma C. Atkinson & Vicent P, 2022. "Structural basis for PoxtA-mediated resistance to phenicol and oxazolidinone antibiotics," Nature Communications, Nature, vol. 13(1), pages 1-13, December.

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