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Genome-encoded ABCF factors implicated in intrinsic antibiotic resistance in Gram-positive bacteria : VmlR2, Ard1 and CplR

Obana, Nozomu ; Takada, Hiraku LU ; Crowe-McAuliffe, Caillan ; Iwamoto, Mizuki ; Egorov, Artyom A LU orcid ; Wu, Kelvin J Y ; Chiba, Shinobu ; Murina, Victoriia ; Paternoga, Helge and Tresco, Ben I C , et al. (2023) In Nucleic Acids Research 51(9). p.4536-4554
Abstract

Genome-encoded antibiotic resistance (ARE) ATP-binding cassette (ABC) proteins of the F subfamily (ARE-ABCFs) mediate intrinsic resistance in diverse Gram-positive bacteria. The diversity of chromosomally-encoded ARE-ABCFs is far from being fully experimentally explored. Here we characterise phylogenetically diverse genome-encoded ABCFs from Actinomycetia (Ard1 from Streptomyces capreolus, producer of the nucleoside antibiotic A201A), Bacilli (VmlR2 from soil bacterium Neobacillus vireti) and Clostridia (CplR from Clostridium perfringens, Clostridium sporogenes and Clostridioides difficile). We demonstrate that Ard1 is a narrow spectrum ARE-ABCF that specifically mediates self-resistance against nucleoside antibiotics. The... (More)

Genome-encoded antibiotic resistance (ARE) ATP-binding cassette (ABC) proteins of the F subfamily (ARE-ABCFs) mediate intrinsic resistance in diverse Gram-positive bacteria. The diversity of chromosomally-encoded ARE-ABCFs is far from being fully experimentally explored. Here we characterise phylogenetically diverse genome-encoded ABCFs from Actinomycetia (Ard1 from Streptomyces capreolus, producer of the nucleoside antibiotic A201A), Bacilli (VmlR2 from soil bacterium Neobacillus vireti) and Clostridia (CplR from Clostridium perfringens, Clostridium sporogenes and Clostridioides difficile). We demonstrate that Ard1 is a narrow spectrum ARE-ABCF that specifically mediates self-resistance against nucleoside antibiotics. The single-particle cryo-EM structure of a VmlR2-ribosome complex allows us to rationalise the resistance spectrum of this ARE-ABCF that is equipped with an unusually long antibiotic resistance determinant (ARD) subdomain. We show that CplR contributes to intrinsic pleuromutilin, lincosamide and streptogramin A resistance in Clostridioides, and demonstrate that C. difficile CplR (CDIF630_02847) synergises with the transposon-encoded 23S ribosomal RNA methyltransferase Erm to grant high levels of antibiotic resistance to the C. difficile 630 clinical isolate. Finally, assisted by uORF4u, our novel tool for detection of upstream open reading frames, we dissect the translational attenuation mechanism that controls the induction of cplR expression upon an antibiotic challenge.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Nucleic Acids Research
volume
51
issue
9
pages
4536 - 4554
publisher
Oxford University Press
external identifiers
  • pmid:36951104
  • scopus:85159769554
ISSN
1362-4962
DOI
10.1093/nar/gkad193
language
English
LU publication?
yes
additional info
© The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research.
id
10079efd-9ef3-4f56-970d-9cfb16ecc743
date added to LUP
2023-03-25 11:16:12
date last changed
2024-04-19 20:32:59
@article{10079efd-9ef3-4f56-970d-9cfb16ecc743,
  abstract     = {{<p>Genome-encoded antibiotic resistance (ARE) ATP-binding cassette (ABC) proteins of the F subfamily (ARE-ABCFs) mediate intrinsic resistance in diverse Gram-positive bacteria. The diversity of chromosomally-encoded ARE-ABCFs is far from being fully experimentally explored. Here we characterise phylogenetically diverse genome-encoded ABCFs from Actinomycetia (Ard1 from Streptomyces capreolus, producer of the nucleoside antibiotic A201A), Bacilli (VmlR2 from soil bacterium Neobacillus vireti) and Clostridia (CplR from Clostridium perfringens, Clostridium sporogenes and Clostridioides difficile). We demonstrate that Ard1 is a narrow spectrum ARE-ABCF that specifically mediates self-resistance against nucleoside antibiotics. The single-particle cryo-EM structure of a VmlR2-ribosome complex allows us to rationalise the resistance spectrum of this ARE-ABCF that is equipped with an unusually long antibiotic resistance determinant (ARD) subdomain. We show that CplR contributes to intrinsic pleuromutilin, lincosamide and streptogramin A resistance in Clostridioides, and demonstrate that C. difficile CplR (CDIF630_02847) synergises with the transposon-encoded 23S ribosomal RNA methyltransferase Erm to grant high levels of antibiotic resistance to the C. difficile 630 clinical isolate. Finally, assisted by uORF4u, our novel tool for detection of upstream open reading frames, we dissect the translational attenuation mechanism that controls the induction of cplR expression upon an antibiotic challenge.</p>}},
  author       = {{Obana, Nozomu and Takada, Hiraku and Crowe-McAuliffe, Caillan and Iwamoto, Mizuki and Egorov, Artyom A and Wu, Kelvin J Y and Chiba, Shinobu and Murina, Victoriia and Paternoga, Helge and Tresco, Ben I C and Nomura, Nobuhiko and Myers, Andrew G and Atkinson, Gemma C and Wilson, Daniel N and Hauryliuk, Vasili}},
  issn         = {{1362-4962}},
  language     = {{eng}},
  month        = {{03}},
  number       = {{9}},
  pages        = {{4536--4554}},
  publisher    = {{Oxford University Press}},
  series       = {{Nucleic Acids Research}},
  title        = {{Genome-encoded ABCF factors implicated in intrinsic antibiotic resistance in Gram-positive bacteria : VmlR2, Ard1 and CplR}},
  url          = {{http://dx.doi.org/10.1093/nar/gkad193}},
  doi          = {{10.1093/nar/gkad193}},
  volume       = {{51}},
  year         = {{2023}},
}