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Structural basis for PoxtA-mediated resistance to phenicol and oxazolidinone antibiotics

Author

Listed:
  • Caillan Crowe-McAuliffe

    (Institute for Biochemistry and Molecular Biology, University of Hamburg)

  • Victoriia Murina

    (Laboratory for Molecular Infection Medicine Sweden (MIMS), Umeå University
    Umeå Centre for Microbial Research (UCMR), Umeå University
    Umeå University)

  • Kathryn Jane Turnbull

    (Laboratory for Molecular Infection Medicine Sweden (MIMS), Umeå University
    Rigshospitalet)

  • Susanne Huch

    (SciLifeLab, Department of Microbiology, Tumor and Cell Biology. Karolinska Institutet)

  • Marje Kasari

    (Laboratory for Molecular Infection Medicine Sweden (MIMS), Umeå University
    Umeå Centre for Microbial Research (UCMR), Umeå University
    University of Tartu, Institute of Technology)

  • Hiraku Takada

    (Laboratory for Molecular Infection Medicine Sweden (MIMS), Umeå University
    Umeå Centre for Microbial Research (UCMR), Umeå University
    Faculty of Life Sciences, Kyoto Sangyo University)

  • Lilit Nersisyan

    (SciLifeLab, Department of Microbiology, Tumor and Cell Biology. Karolinska Institutet)

  • Arnfinn Sundsfjord

    (Norwegian National Advisory Unit on Detection of Antimicrobial Resistance, University Hospital of North Norway
    Research Group for Host-Microbe Interactions, Department of Medical Biology, Faculty of Health Sciences, UiT The Arctic University of Norway)

  • Kristin Hegstad

    (Norwegian National Advisory Unit on Detection of Antimicrobial Resistance, University Hospital of North Norway
    Research Group for Host-Microbe Interactions, Department of Medical Biology, Faculty of Health Sciences, UiT The Arctic University of Norway)

  • Gemma C. Atkinson

    (Umeå Centre for Microbial Research (UCMR), Umeå University
    Lund University)

  • Vicent Pelechano

    (SciLifeLab, Department of Microbiology, Tumor and Cell Biology. Karolinska Institutet)

  • Daniel N. Wilson

    (Institute for Biochemistry and Molecular Biology, University of Hamburg)

  • Vasili Hauryliuk

    (Laboratory for Molecular Infection Medicine Sweden (MIMS), Umeå University
    Umeå Centre for Microbial Research (UCMR), Umeå University
    Umeå University
    University of Tartu, Institute of Technology)

Abstract

PoxtA and OptrA are ATP binding cassette (ABC) proteins of the F subtype (ABCF). They confer resistance to oxazolidinone and phenicol antibiotics, such as linezolid and chloramphenicol, which stall translating ribosomes when certain amino acids are present at a defined position in the nascent polypeptide chain. These proteins are often encoded on mobile genetic elements, facilitating their rapid spread amongst Gram-positive bacteria, and are thought to confer resistance by binding to the ribosome and dislodging the bound antibiotic. However, the mechanistic basis of this resistance remains unclear. Here we refine the PoxtA spectrum of action, demonstrate alleviation of linezolid-induced context-dependent translational stalling, and present cryo-electron microscopy structures of PoxtA in complex with the Enterococcus faecalis 70S ribosome. PoxtA perturbs the CCA-end of the P-site tRNA, causing it to shift by ∼4 Å out of the ribosome, corresponding to a register shift of approximately one amino acid for an attached nascent polypeptide chain. We postulate that the perturbation of the P-site tRNA by PoxtA thereby alters the conformation of the attached nascent chain to disrupt the drug binding site.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-29274-9
    DOI: 10.1038/s41467-022-29274-9
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    References listed on IDEAS

    as
    1. 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.
    2. Alexey Rozov & Natalia Demeshkina & Iskander Khusainov & Eric Westhof & Marat Yusupov & Gulnara Yusupova, 2016. "Novel base-pairing interactions at the tRNA wobble position crucial for accurate reading of the genetic code," Nature Communications, Nature, vol. 7(1), pages 1-10, April.
    3. Michael Graf & Paul Huter & Cristina Maracci & Miroslav Peterek & Marina V. Rodnina & Daniel N. Wilson, 2018. "Visualization of translation termination intermediates trapped by the Apidaecin 137 peptide during RF3-mediated recycling of RF1," Nature Communications, Nature, vol. 9(1), pages 1-11, December.
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    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.

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