6QUL

Structure of a bacterial 50S ribosomal subunit in complex with the novel quinoxolidinone antibiotic cadazolid

6QUL の概要

• エントリーDOI: 10.2210/pdb6qul/pdb
• EMDBエントリー: 4638
• 分子名称: P-site fMet-tRNA(fMet), 50S ribosomal protein L13, 50S ribosomal protein L14, ... (36 entities in total)
• 機能のキーワード: ribosome, cadazolid, quinoxolidinone, 50s, antibiotic
• 由来する生物種: Escherichia coli; 詳細
• タンパク質・核酸の鎖数: 31
• 化学式量合計: 1319248.07

構造登録者

Scaiola, A.,Leibundgut, M.,Boehringer, D.,Ritz, D. (登録日: 2019-02-27, 公開日: 2019-04-10, 最終更新日: 2025-12-17)

主引用文献

Scaiola, A.,Leibundgut, M.,Boehringer, D.,Caspers, P.,Bur, D.,Locher, H.H.,Rueedi, G.,Ritz, D.
Structural basis of translation inhibition by cadazolid, a novel quinoxolidinone antibiotic.
Sci Rep, 9:5634-5634, 2019

PubMed Abstract: Oxazolidinones are synthetic antibiotics used for treatment of infections caused by Gram-positive bacteria. They target the bacterial protein synthesis machinery by binding to the peptidyl transferase centre (PTC) of the ribosome and interfering with the peptidyl transferase reaction. Cadazolid is the first member of quinoxolidinone antibiotics, which are characterized by combining the pharmacophores of oxazolidinones and fluoroquinolones, and it is evaluated for treatment of Clostridium difficile gastrointestinal infections that frequently occur in hospitalized patients. In vitro protein synthesis inhibition by cadazolid was shown in Escherichia coli and Staphylococcus aureus, including an isolate resistant against linezolid, the prototypical oxazolidinone antibiotic. To better understand the mechanism of inhibition, we determined a 3.0 Å cryo-electron microscopy structure of cadazolid bound to the E. coli ribosome in complex with mRNA and initiator tRNA. Here we show that cadazolid binds with its oxazolidinone moiety in a binding pocket in close vicinity of the PTC as observed previously for linezolid, and that it extends its unique fluoroquinolone moiety towards the A-site of the PTC. In this position, the drug inhibits protein synthesis by interfering with the binding of tRNA to the A-site, suggesting that its chemical features also can enable the inhibition of linezolid-resistant strains.

PubMed: 30948752
DOI: 10.1038/s41598-019-42155-4

実験手法

ELECTRON MICROSCOPY (3 Å)