8g2d

Publication Abstract from PubMed

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.

Structural basis of Cfr-mediated antimicrobial resistance and mechanisms to evade it.,Aleksandrova EV, Wu KJY, Tresco BIC, Syroegin EA, Killeavy EE, Balasanyants SM, Svetlov MS, Gregory ST, Atkinson GC, Myers AG, Polikanov YS Nat Chem Biol. 2024 Jul;20(7):867-876. doi: 10.1038/s41589-023-01525-w. Epub 2024 , Jan 18. PMID:38238495^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.