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Structural basis of Cfr-mediated antimicrobial resistance and mechanisms to evade it

Aleksandrova, Elena V. ; Wu, Kelvin J.Y. ; Tresco, Ben I.C. ; Syroegin, Egor A. ; Killeavy, Erin E. ; Balasanyants, Samson M. ; Svetlov, Maxim S. ; Gregory, Steven T. ; Atkinson, Gemma C. LU and Myers, Andrew G. , et al. (2024) In Nature Chemical Biology
Abstract

The bacterial ribosome is an essential drug target as many clinically important antibiotics bind and inhibit its functional centers. The catalytic peptidyl transferase center (PTC) is targeted by the broadest array of inhibitors belonging to several chemical classes. One of the most abundant and clinically prevalent resistance mechanisms to PTC-acting drugs in Gram-positive bacteria is C8-methylation of the universally conserved A2503 nucleobase by Cfr methylase in 23S ribosomal RNA. Despite its clinical importance, a sufficient understanding of the molecular mechanisms underlying Cfr-mediated resistance is currently lacking. Here, we report a set of high-resolution structures of the Cfr-modified 70S ribosome containing aminoacyl- and... (More)

The bacterial ribosome is an essential drug target as many clinically important antibiotics bind and inhibit its functional centers. The catalytic peptidyl transferase center (PTC) is targeted by the broadest array of inhibitors belonging to several chemical classes. One of the most abundant and clinically prevalent resistance mechanisms to PTC-acting drugs in Gram-positive bacteria is C8-methylation of the universally conserved A2503 nucleobase by Cfr methylase in 23S ribosomal RNA. Despite its clinical importance, a sufficient understanding of the molecular mechanisms underlying Cfr-mediated resistance is currently lacking. Here, we report a set of high-resolution structures of the Cfr-modified 70S ribosome containing aminoacyl- and peptidyl-transfer RNAs. These structures reveal an allosteric rearrangement of nucleotide A2062 upon Cfr-mediated methylation of A2503 that likely contributes to the reduced potency of some PTC inhibitors. Additionally, we provide the structural bases behind two distinct mechanisms of engaging the Cfr-methylated ribosome by the antibiotics iboxamycin and tylosin.

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publication status
epub
subject
in
Nature Chemical Biology
publisher
Nature Publishing Group
external identifiers
  • pmid:38238495
  • scopus:85182433532
ISSN
1552-4450
DOI
10.1038/s41589-023-01525-w
language
English
LU publication?
yes
id
e6b8fa50-3f1c-476f-9b16-2b6df3a672ad
date added to LUP
2024-02-16 13:52:08
date last changed
2024-04-23 16:09:58
@article{e6b8fa50-3f1c-476f-9b16-2b6df3a672ad,
  abstract     = {{<p>The bacterial ribosome is an essential drug target as many clinically important antibiotics bind and inhibit its functional centers. The catalytic peptidyl transferase center (PTC) is targeted by the broadest array of inhibitors belonging to several chemical classes. One of the most abundant and clinically prevalent resistance mechanisms to PTC-acting drugs in Gram-positive bacteria is C8-methylation of the universally conserved A2503 nucleobase by Cfr methylase in 23S ribosomal RNA. Despite its clinical importance, a sufficient understanding of the molecular mechanisms underlying Cfr-mediated resistance is currently lacking. Here, we report a set of high-resolution structures of the Cfr-modified 70S ribosome containing aminoacyl- and peptidyl-transfer RNAs. These structures reveal an allosteric rearrangement of nucleotide A2062 upon Cfr-mediated methylation of A2503 that likely contributes to the reduced potency of some PTC inhibitors. Additionally, we provide the structural bases behind two distinct mechanisms of engaging the Cfr-methylated ribosome by the antibiotics iboxamycin and tylosin. <br/></p>}},
  author       = {{Aleksandrova, Elena V. and Wu, Kelvin J.Y. and Tresco, Ben I.C. and Syroegin, Egor A. and Killeavy, Erin E. and Balasanyants, Samson M. and Svetlov, Maxim S. and Gregory, Steven T. and Atkinson, Gemma C. and Myers, Andrew G. and Polikanov, Yury S.}},
  issn         = {{1552-4450}},
  language     = {{eng}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature Chemical Biology}},
  title        = {{Structural basis of Cfr-mediated antimicrobial resistance and mechanisms to evade it}},
  url          = {{http://dx.doi.org/10.1038/s41589-023-01525-w}},
  doi          = {{10.1038/s41589-023-01525-w}},
  year         = {{2024}},
}