8FC4

Crystal structure of the A2058-N6-dimethylated Thermus thermophilus 70S ribosome in complex with protein Y, hygromycin A, and erythromycin at 2.45A resolution

これはPDB形式変換不可エントリーです。

8FC4 の概要

• エントリーDOI: 10.2210/pdb8fc4/pdb
• 分子名称: 23S Ribosomal RNA, 50S ribosomal protein L14, 50S ribosomal protein L15, ... (61 entities in total)
• 機能のキーワード: hygromycin a; macrolides; ketolides; erythromycin; azithromycin; telithromycin; antibiotic; synergy; erm methyltransferase, x-ray structure; 70s ribosome; peptidyl transferase center; nascent peptide exit tunnel, ribosome
• 由来する生物種: Escherichia coli K-12; 詳細
• タンパク質・核酸の鎖数: 106
• 化学式量合計: 4426447.13

構造登録者

Chen, C.-W.,Syroegin, E.A.,Svetlov, M.S.,Polikanov, Y.S. (登録日: 2022-12-01, 公開日: 2023-07-26)

主引用文献

Chen, C.W.,Leimer, N.,Syroegin, E.A.,Dunand, C.,Bulman, Z.P.,Lewis, K.,Polikanov, Y.S.,Svetlov, M.S.
Structural insights into the mechanism of overcoming Erm-mediated resistance by macrolides acting together with hygromycin-A.
Nat Commun, 14:4196-4196, 2023

PubMed Abstract: The ever-growing rise of antibiotic resistance among bacterial pathogens is one of the top healthcare threats today. Although combination antibiotic therapies represent a potential approach to more efficiently combat infections caused by susceptible and drug-resistant bacteria, only a few known drug pairs exhibit synergy/cooperativity in killing bacteria. Here, we discover that well-known ribosomal antibiotics, hygromycin A (HygA) and macrolides, which target peptidyl transferase center and peptide exit tunnel, respectively, can act cooperatively against susceptible and drug-resistant bacteria. Remarkably, HygA slows down macrolide dissociation from the ribosome by 60-fold and enhances the otherwise weak antimicrobial activity of the newest-generation macrolide drugs known as ketolides against macrolide-resistant bacteria. By determining a set of high-resolution X-ray crystal structures of drug-sensitive wild-type and macrolide-resistant Erm-methylated 70S ribosomes in complex with three HygA-macrolide pairs, we provide a structural rationale for the binding cooperativity of these drugs and also uncover the molecular mechanism of overcoming Erm-type resistance by macrolides acting together with hygromycin A. Altogether our structural, biochemical, and microbiological findings lay the foundation for the subsequent development of synergistic antibiotic tandems with improved bactericidal properties against drug-resistant pathogens, including those expressing erm genes.

PubMed: 37452045
DOI: 10.1038/s41467-023-39653-5

実験手法

X-RAY DIFFRACTION (2.45 Å)