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

Publication Type:

Journal Article

Authors:

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; Myers, Andrew G; Polikanov, Yury S

Source:

Nat Chem Biol, Volume 20, Issue 7, p.867-876 (2024)

Keywords:

Anti-Bacterial Agents, Drug Resistance, Bacterial, Escherichia coli, Escherichia coli Proteins, Methylation, Methyltransferases, Models, Molecular, Ribosomes, RNA, Ribosomal, 23S

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.</p>

PDB: 
8G29 for the A2503-C2,C8-dimethylated T. thermophilus 70S ribosome in complex with mRNA, aminoacylated A-site Phe-NH-tRNAPhe, aminoacylated P-site fMet-NH-tRNAiMet and deacylated E-site tRNAPhe; 8G2A for the A2503-C2,C8-dimethylated T. thermophilus 70S ribosome in complex with mRNA, aminoacylated A-site Phe-NH-tRNAPhe, peptidyl P-site fMTHSMRC-NH-tRNAiMet and deacylated E-site tRNAPhe. 8G2B for the A2503-C2,C8-dimethylated T. thermophilus 70S ribosome in complex with mRNA, deacylated A-site tRNAPhe, aminoacylated P-site fMet-NH-tRNAiMet, deacylated E-site tRNAPhe and iboxamycin; 8G2C for the A2503-C2,C8-dimethylated T. thermophilus 70S ribosome in complex with mRNA, aminoacylated A-site Phe-NH-tRNAPhe, aminoacylated P-site fMet-NH-tRNAiMet, deacylated E-site tRNAPhe and tylosin; 8G2D for the wild-type T. thermophilus 70S ribosome in complex with mRNA, deacylated A-site tRNAPhe, deacylated P-site tRNAiMet, deacylated E-site tRNAPhe and tylosin.
Detector: 
EIGER2
Beamline: 
24-ID-C
24-ID-E