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Title | Molecular basis of the pleiotropic effects by the antibiotic amikacin on the ribosome. |
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Journal, issue, pages | Nat Commun, Vol. 14, Issue 1, Page 4666, Year 2023 |
Publish date | Aug 3, 2023 |
Authors | Savannah M Seely / Narayan P Parajuli / Arindam De Tarafder / Xueliang Ge / Suparna Sanyal / Matthieu G Gagnon / |
PubMed Abstract | Aminoglycosides are a class of antibiotics that bind to ribosomal RNA and exert pleiotropic effects on ribosome function. Amikacin, the semisynthetic derivative of kanamycin, is commonly used for ...Aminoglycosides are a class of antibiotics that bind to ribosomal RNA and exert pleiotropic effects on ribosome function. Amikacin, the semisynthetic derivative of kanamycin, is commonly used for treating severe infections with multidrug-resistant, aerobic Gram-negative bacteria. Amikacin carries the 4-amino-2-hydroxy butyrate (AHB) moiety at the N amino group of the central 2-deoxystreptamine (2-DOS) ring, which may confer amikacin a unique ribosome inhibition profile. Here we use in vitro fast kinetics combined with X-ray crystallography and cryo-EM to dissect the mechanisms of ribosome inhibition by amikacin and the parent compound, kanamycin. Amikacin interferes with tRNA translocation, release factor-mediated peptidyl-tRNA hydrolysis, and ribosome recycling, traits attributed to the additional interactions amikacin makes with the decoding center. The binding site in the large ribosomal subunit proximal to the 3'-end of tRNA in the peptidyl (P) site lays the groundwork for rational design of amikacin derivatives with improved antibacterial properties. |
External links | Nat Commun / PubMed:37537169 / PubMed Central |
Methods | EM (single particle) / X-ray diffraction |
Resolution | 2.89 - 2.946 Å |
Structure data | EMDB-40882, PDB-8syl: PDB-8ev6: PDB-8ev7: |
Chemicals | ChemComp-MG: ChemComp-AKN: ChemComp-ZN: ChemComp-SF4: ChemComp-HOH: ChemComp-KAN: ChemComp-PHE: |
Source |
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Keywords | RIBOSOME / Amikacin / antibiotic / aminoglycoside / 70S ribosome / inhibitor / tRNA / Kanamycin / cryo-EM |