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

Caillan Crowe-McAuliffe, Victoriia Murina, Kathryn Jane Turnbull, Marje Kasari, Merianne Mohamad, Christine Polte, Hiraku Takada, Karolis Vaitkevicius, Jörgen Johansson, Zoya Ignatova, Gemma C. Atkinson, Alex J. O’Neill, Vasili Hauryliuk () and Daniel N. Wilson ()
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Caillan Crowe-McAuliffe: University of Hamburg
Victoriia Murina: Umeå University
Kathryn Jane Turnbull: Umeå University
Marje Kasari: University of Tartu, Institute of Technology
Merianne Mohamad: University of Leeds
Christine Polte: University of Hamburg
Hiraku Takada: Umeå University
Karolis Vaitkevicius: Umeå University
Jörgen Johansson: Umeå University
Zoya Ignatova: University of Hamburg
Gemma C. Atkinson: Umeå University
Alex J. O’Neill: University of Leeds
Vasili Hauryliuk: Umeå University
Daniel N. Wilson: University of Hamburg

Nature Communications, 2021, vol. 12, issue 1, 1-14

Abstract: 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.

Date: 2021
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-23753-1

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DOI: 10.1038/s41467-021-23753-1

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