Skip to main content

Lund University Publications

LUND UNIVERSITY LIBRARIES

Structural basis of Cfr-mediated antimicrobial resistance and mechanisms for its evasion

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. (2023)
Abstract

The ribosome is an essential drug target as many classes of 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 mechanisms of resistance to PTC-acting drugs is C8-methylation of the universally conserved adenine residue 2503 (A2503) of the 23S rRNA by the methyltransferase Cfr. Despite its clinical significance, a sufficient understanding of the molecular mechanisms underlying Cfr-mediated resistance is currently lacking. In this work, we developed a method to express a functionally-active Cfr-methyltransferase in the thermophilic... (More)

The ribosome is an essential drug target as many classes of 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 mechanisms of resistance to PTC-acting drugs is C8-methylation of the universally conserved adenine residue 2503 (A2503) of the 23S rRNA by the methyltransferase Cfr. Despite its clinical significance, a sufficient understanding of the molecular mechanisms underlying Cfr-mediated resistance is currently lacking. In this work, we developed a method to express a functionally-active Cfr-methyltransferase in the thermophilic bacterium
Thermus thermophilus and report a set of high-resolution structures of the Cfr-modified 70S ribosome containing aminoacyl- and peptidyl-tRNAs. Our structures reveal that an allosteric rearrangement of nucleotide A2062 upon Cfr-methylation of A2503 is likely responsible for the inability of some PTC inhibitors to bind to the ribosome, providing additional insights into the Cfr resistance mechanism. Lastly, by determining the structures of the Cfr-methylated ribosome in complex with the antibiotics iboxamycin and tylosin, we provide the structural bases behind two distinct mechanisms of evading Cfr-mediated resistance.

(Less)
Please use this url to cite or link to this publication:
author
; ; ; ; ; ; ; ; and , et al. (More)
; ; ; ; ; ; ; ; ; and (Less)
organization
publishing date
type
Working paper/Preprint
publication status
published
subject
publisher
bioRxiv
external identifiers
  • pmid:37808676
DOI
10.1101/2023.09.27.559749
language
English
LU publication?
yes
id
5f5e3dbc-f09c-4f86-9504-7d227a9de075
date added to LUP
2024-05-21 15:11:01
date last changed
2024-05-21 15:51:01
@misc{5f5e3dbc-f09c-4f86-9504-7d227a9de075,
  abstract     = {{<p>The ribosome is an essential drug target as many classes of 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 mechanisms of resistance to PTC-acting drugs is C8-methylation of the universally conserved adenine residue 2503 (A2503) of the 23S rRNA by the methyltransferase Cfr. Despite its clinical significance, a sufficient understanding of the molecular mechanisms underlying Cfr-mediated resistance is currently lacking. In this work, we developed a method to express a functionally-active Cfr-methyltransferase in the thermophilic bacterium <br>
 Thermus thermophilus and report a set of high-resolution structures of the Cfr-modified 70S ribosome containing aminoacyl- and peptidyl-tRNAs. Our structures reveal that an allosteric rearrangement of nucleotide A2062 upon Cfr-methylation of A2503 is likely responsible for the inability of some PTC inhibitors to bind to the ribosome, providing additional insights into the Cfr resistance mechanism. Lastly, by determining the structures of the Cfr-methylated ribosome in complex with the antibiotics iboxamycin and tylosin, we provide the structural bases behind two distinct mechanisms of evading Cfr-mediated resistance.<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}},
  language     = {{eng}},
  month        = {{09}},
  note         = {{Preprint}},
  publisher    = {{bioRxiv}},
  title        = {{Structural basis of Cfr-mediated antimicrobial resistance and mechanisms for its evasion}},
  url          = {{http://dx.doi.org/10.1101/2023.09.27.559749}},
  doi          = {{10.1101/2023.09.27.559749}},
  year         = {{2023}},
}