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Structural basis of ABCF-mediated resistance to pleuromutilin, lincosamide, and streptogramin A antibiotics in Gram-positive pathogens
Institute for Biochemistry and Molecular Biology, University of Hamburg, Hamburg, Germany.
Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).ORCID iD: 0000-0003-1523-1816
Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
University of Tartu, Institute of Technology, Tartu, Estonia.
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2021 (English)In: Nature Communications, E-ISSN 2041-1723, Vol. 12, no 1, article id 3577Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
Springer Nature, 2021. Vol. 12, no 1, article id 3577
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Biochemistry and Molecular Biology
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URN: urn:nbn:se:umu:diva-184901DOI: 10.1038/s41467-021-23753-1ISI: 000663757400003Scopus ID: 2-s2.0-85107814945OAI: oai:DiVA.org:umu-184901DiVA, id: diva2:1571106
Available from: 2021-06-22 Created: 2021-06-22 Last updated: 2023-09-05Bibliographically approved

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Murina, VictoriiaTurnbull, Kathryn JaneTakada, HirakuVaitkevicius, KarolisJohansson, JörgenAtkinson, Gemma C.Hauryliuk, Vasili

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Murina, VictoriiaTurnbull, Kathryn JaneTakada, HirakuVaitkevicius, KarolisJohansson, JörgenAtkinson, Gemma C.Hauryliuk, Vasili
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Molecular Infection Medicine Sweden (MIMS)Department of Molecular Biology (Faculty of Medicine)
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