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

Author

Listed:
  • 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
    University of Texas Medical Branch
    University of Texas Medical Branch
    University of Texas Medical Branch)

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.

Suggested Citation

  • Savannah M. Seely & Narayan P. Parajuli & Arindam Tarafder & Xueliang Ge & Suparna Sanyal & Matthieu G. Gagnon, 2023. "Molecular basis of the pleiotropic effects by the antibiotic amikacin on the ribosome," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-40416-5
    DOI: 10.1038/s41467-023-40416-5
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    References listed on IDEAS

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    1. Michael R. Wasserman & Arto Pulk & Zhou Zhou & Roger B. Altman & John C. Zinder & Keith D. Green & Sylvie Garneau-Tsodikova & Jamie H. Doudna Cate & Scott C. Blanchard, 2015. "Chemically related 4,5-linked aminoglycoside antibiotics drive subunit rotation in opposite directions," Nature Communications, Nature, vol. 6(1), pages 1-12, November.
    2. Valentyn Petrychenko & Bee-Zen Peng & Ana C. A. P. Schwarzer & Frank Peske & Marina V. Rodnina & Niels Fischer, 2021. "Structural mechanism of GTPase-powered ribosome-tRNA movement," Nature Communications, Nature, vol. 12(1), pages 1-9, December.
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