Mechanistic insights into translation inhibition by aminoglycoside antibiotic arbekacin.
Nucleic Acids Res
; 49(12): 6880-6892, 2021 07 09.
Article
de En
| MEDLINE
| ID: mdl-34125898
ABSTRACT
How aminoglycoside antibiotics limit bacterial growth and viability is not clearly understood. Here we employ fast kinetics to reveal the molecular mechanism of action of a clinically used, new-generation, semisynthetic aminoglycoside Arbekacin (ABK), which is designed to avoid enzyme-mediated deactivation common to other aminoglycosides. Our results portray complete picture of ABK inhibition of bacterial translation with precise quantitative characterizations. We find that ABK inhibits different steps of translation in nanomolar to micromolar concentrations by imparting pleotropic effects. ABK binding stalls elongating ribosomes to a state, which is unfavorable for EF-G binding. This prolongs individual translocation step from â¼50 ms to at least 2 s; the mean time of translocation increases inversely with EF-G concentration. ABK also inhibits translation termination by obstructing RF1/RF2 binding to the ribosome. Furthermore, ABK decreases accuracy of mRNA decoding (UUC vs. CUC) by â¼80 000 fold, causing aberrant protein production. Importantly, translocation and termination events cannot be completely stopped even with high ABK concentration. Extrapolating our kinetic model of ABK action, we postulate that aminoglycosides impose bacteriostatic effect mainly by inhibiting translocation, while they become bactericidal in combination with decoding errors.
Texte intégral:
1
Collection:
01-internacional
Base de données:
MEDLINE
Sujet principal:
Ribosomes
/
Biosynthèse des protéines
/
Inhibiteurs de la synthèse protéique
/
Dibékacine
/
Antibactériens
Type d'étude:
Prognostic_studies
Langue:
En
Journal:
Nucleic Acids Res
Année:
2021
Type de document:
Article
Pays d'affiliation:
Suède