Structural basis of Cfr-mediated antimicrobial resistance and mechanisms to evade it
(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.
(Less)
- author
- organization
- publishing date
- 2024
- type
- Contribution to journal
- publication status
- epub
- subject
- in
- Nature Chemical Biology
- publisher
- Nature Publishing Group
- external identifiers
-
- scopus:85182433532
- pmid:38238495
- 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
- 2024-10-09 10:10:30
@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}}, }