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Sal-type ABC-F proteins : Intrinsic and common mediators of pleuromutilin resistance by target protection in staphylococci

Mohamad, Merianne ; Nicholson, David ; Saha, Chayan Kumar LU orcid ; Hauryliuk, Vasili LU orcid ; Edwards, Thomas A ; Atkinson, Gemma C LU ; Ranson, Neil A and O'Neill, Alex J (2022) In Nucleic Acids Research 50(4). p.2128-2142
Abstract

The first member of the pleuromutilin (PLM) class suitable for systemic antibacterial chemotherapy in humans recently entered clinical use, underscoring the need to better understand mechanisms of PLM resistance in disease-causing bacterial genera. Of the proteins reported to mediate PLM resistance in staphylococci, the least-well studied to date is Sal(A), a putative ABC-F NTPase that-by analogy to other proteins of this type-may act to protect the ribosome from PLMs. Here, we establish the importance of Sal proteins as a common source of PLM resistance across multiple species of staphylococci. Sal(A) is revealed as but one member of a larger group of Sal-type ABC-F proteins that vary considerably in their ability to mediate resistance... (More)

The first member of the pleuromutilin (PLM) class suitable for systemic antibacterial chemotherapy in humans recently entered clinical use, underscoring the need to better understand mechanisms of PLM resistance in disease-causing bacterial genera. Of the proteins reported to mediate PLM resistance in staphylococci, the least-well studied to date is Sal(A), a putative ABC-F NTPase that-by analogy to other proteins of this type-may act to protect the ribosome from PLMs. Here, we establish the importance of Sal proteins as a common source of PLM resistance across multiple species of staphylococci. Sal(A) is revealed as but one member of a larger group of Sal-type ABC-F proteins that vary considerably in their ability to mediate resistance to PLMs and other antibiotics. We find that specific sal genes are intrinsic to particular staphylococcal species, and show that this gene family is likely ancestral to the genus Staphylococcus. Finally, we solve the cryo-EM structure of a representative Sal-type protein (Sal(B)) in complex with the staphylococcal 70S ribosome, revealing that Sal-type proteins bind into the E site to mediate target protection, likely by displacing PLMs and other antibiotics via an allosteric mechanism.

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author
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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Nucleic Acids Research
volume
50
issue
4
article number
gkac058
pages
2128 - 2142
publisher
Oxford University Press
external identifiers
  • scopus:85125431255
  • pmid:35137182
ISSN
1362-4962
DOI
10.1093/nar/gkac058
language
English
LU publication?
yes
id
0366bbef-560a-474b-9776-32996b360a0c
date added to LUP
2022-02-15 07:42:01
date last changed
2024-06-19 05:04:04
@article{0366bbef-560a-474b-9776-32996b360a0c,
  abstract     = {{<p>The first member of the pleuromutilin (PLM) class suitable for systemic antibacterial chemotherapy in humans recently entered clinical use, underscoring the need to better understand mechanisms of PLM resistance in disease-causing bacterial genera. Of the proteins reported to mediate PLM resistance in staphylococci, the least-well studied to date is Sal(A), a putative ABC-F NTPase that-by analogy to other proteins of this type-may act to protect the ribosome from PLMs. Here, we establish the importance of Sal proteins as a common source of PLM resistance across multiple species of staphylococci. Sal(A) is revealed as but one member of a larger group of Sal-type ABC-F proteins that vary considerably in their ability to mediate resistance to PLMs and other antibiotics. We find that specific sal genes are intrinsic to particular staphylococcal species, and show that this gene family is likely ancestral to the genus Staphylococcus. Finally, we solve the cryo-EM structure of a representative Sal-type protein (Sal(B)) in complex with the staphylococcal 70S ribosome, revealing that Sal-type proteins bind into the E site to mediate target protection, likely by displacing PLMs and other antibiotics via an allosteric mechanism.</p>}},
  author       = {{Mohamad, Merianne and Nicholson, David and Saha, Chayan Kumar and Hauryliuk, Vasili and Edwards, Thomas A and Atkinson, Gemma C and Ranson, Neil A and O'Neill, Alex J}},
  issn         = {{1362-4962}},
  language     = {{eng}},
  month        = {{02}},
  number       = {{4}},
  pages        = {{2128--2142}},
  publisher    = {{Oxford University Press}},
  series       = {{Nucleic Acids Research}},
  title        = {{Sal-type ABC-F proteins : Intrinsic and common mediators of pleuromutilin resistance by target protection in staphylococci}},
  url          = {{http://dx.doi.org/10.1093/nar/gkac058}},
  doi          = {{10.1093/nar/gkac058}},
  volume       = {{50}},
  year         = {{2022}},
}