Molecular basis of the pleiotropic effects by the antibiotic amikacin on the ribosome

Savannah M. Seely, Narayan P. Parajuli, Arindam Tarafder, Xueliang Ge, Suparna Sanyal () and Matthieu G. Gagnon ()
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Savannah M. Seely: University of Texas Medical Branch
Narayan P. Parajuli: Uppsala University
Arindam Tarafder: Uppsala University
Xueliang Ge: Uppsala University
Suparna Sanyal: Uppsala University
Matthieu G. Gagnon: University of Texas Medical Branch

Nature Communications, 2023, vol. 14, issue 1, 1-12

Abstract: 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 treating severe infections with multidrug-resistant, aerobic Gram-negative bacteria. Amikacin carries the 4-amino-2-hydroxy butyrate (AHB) moiety at the N1 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.

Date: 2023
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DOI: 10.1038/s41467-023-40416-5

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