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Evidence That Antibiotics Bind to Human Mitochondrial Ribosomal RNA Has Implications for Aminoglycoside Toxicity

Seoyeon Hong1, Kimberly A Harris1, Kathryn D Fanning1

  • 1From The RNA Institute and the Department of Biological Sciences, University at Albany, Albany, New York 12222.

The Journal of Biological Chemistry
|June 11, 2015
PubMed

Insights

Aminoglycoside antibiotics bind human mitochondrial helix69 similarly to bacterial helix69, suggesting a role in toxicity. This interaction enhances mitochondrial helix69 stability and alters its conformation, offering new insights into drug side effects.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Pharmacology

Background:

  • Aminoglycosides are crucial antibiotics targeting bacterial ribosomes.
  • Their toxicity is a concern, potentially linked to interactions with human ribosomal RNA.
  • The role of aminoglycoside binding to human helix69 remains largely unexplored.

Purpose of the Study:

  • To investigate the binding of aminoglycosides to human cytoplasmic and mitochondrial helix69.
  • To compare these interactions with those in Escherichia coli helix69.
  • To elucidate the structural and conformational changes induced by aminoglycoside binding and their link to toxicity.

Main Methods:

  • Chemical synthesis of terminal hairpins of human cytoplasmic, human mitochondrial, and E. coli helix69.
  • Binding affinity measurements using dissociation constants.
  • Analysis of thermal stability, base stacking, and conformation.
  • Proton one-dimensional and two-dimensional Nuclear Magnetic Resonance (NMR) spectroscopy.

Main Results:

  • Aminoglycosides (gentamicin, kanamycin A) exhibited similar dissociation constants for human cytoplasmic, human mitochondrial, and E. coli helix69.
  • Aminoglycoside binding increased the conformational stability of human mitochondrial helix69 via enhanced base stacking.
  • NMR revealed specific conformational changes in human mitochondrial and E. coli helix69, distinct from human cytoplasmic helix69.

Conclusions:

  • Aminoglycoside binding affinity to human mitochondrial helix69 mirrors that of bacterial helix69.
  • The observed increase in structural stability and conformational changes in human mitochondrial helix69 suggest a significant role in aminoglycoside-induced toxicity.
  • These findings provide a molecular basis for understanding aminoglycoside side effects.
Keywords:
antibiotic actioncircular dichroism (CD)nuclear magnetic resonance (NMR)ribosomal ribonucleic acid (rRNA) (ribosomal RNA)translation

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