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

Crowe-McAuliffe, Caillan ; Murina, Victoriia ; Turnbull, Kathryn Jane ; Kasari, Marje ; Mohamad, Merianne ; Polte, Christine ; Takada, Hiraku ; Vaitkevicius, Karolis ; Johansson, Jörgen LU and Ignatova, Zoya , et al. (2021) In Nature Communications 12(1).
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... (More)

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.

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publishing date
type
Contribution to journal
publication status
published
subject
in
Nature Communications
volume
12
issue
1
article number
3577
publisher
Nature Publishing Group
external identifiers
  • scopus:85107814945
  • pmid:34117249
ISSN
2041-1723
DOI
10.1038/s41467-021-23753-1
language
English
LU publication?
yes
id
0da93bad-dbbe-4681-8dac-a15025130bfa
date added to LUP
2021-06-29 10:23:57
date last changed
2024-06-16 15:39:08
@article{0da93bad-dbbe-4681-8dac-a15025130bfa,
  abstract     = {{<p>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 VgaA<sub>LC</sub> 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.</p>}},
  author       = {{Crowe-McAuliffe, Caillan and Murina, Victoriia and Turnbull, Kathryn Jane and Kasari, Marje and Mohamad, Merianne and Polte, Christine and Takada, Hiraku and Vaitkevicius, Karolis and Johansson, Jörgen and Ignatova, Zoya and Atkinson, Gemma C. and O’Neill, Alex J. and Hauryliuk, Vasili and Wilson, Daniel N.}},
  issn         = {{2041-1723}},
  language     = {{eng}},
  number       = {{1}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature Communications}},
  title        = {{Structural basis of ABCF-mediated resistance to pleuromutilin, lincosamide, and streptogramin A antibiotics in Gram-positive pathogens}},
  url          = {{http://dx.doi.org/10.1038/s41467-021-23753-1}},
  doi          = {{10.1038/s41467-021-23753-1}},
  volume       = {{12}},
  year         = {{2021}},
}