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A minimum structure of aminoglycosides that causes an initiation shift of trans-translation

Takayuki Konno1, Toshiharu Takahashi, Daisuke Kurita

  • 1Department of Biochemistry and Biotechnology, Faculty of Agriculture and Life Science Hirosaki University, Hirosaki 036-8561, Japan.

Nucleic Acids Research
|August 6, 2004
PubMed

Insights

Certain aminoglycoside antibiotics, like paromomycin, can alter bacterial trans-translation (a cellular repair process). This study reveals how different aminoglycosides affect this process by interacting with the ribosome, impacting translation resumption.

Area of Science:

  • Molecular Biology
  • Microbiology
  • Biochemistry

Background:

  • Trans-translation is a crucial bacterial mechanism that rescues stalled ribosomes.
  • Aminoglycoside antibiotics can interfere with bacterial translation.
  • Paromomycin, a 4,5-disubstituted aminoglycoside, was previously shown to induce a -1 shift in trans-translation initiation.

Purpose of the Study:

  • To investigate the molecular basis of aminoglycoside-induced shifts in trans-translation initiation.
  • To determine which structural features of aminoglycosides are responsible for their effects on trans-translation.
  • To correlate aminoglycoside effects with ribosome A-site conformational changes.

Main Methods:

  • In vitro analysis of trans-translation in the presence of various aminoglycosides.
  • Assessment of translation resumption points on transfer-messenger RNA (tmRNA).
  • Correlation of observed effects with existing structural data on ribosome A-site conformation.

Main Results:

  • 4,5- and 4,6-disubstituted aminoglycosides (paromomycin, tobramycin, gentamicin) induced initiation shifts in trans-translation.
  • Neamine, containing essential structural elements (rings I and II), was sufficient to cause shifts.
  • Aminoglycosides that induced shifts (paromomycin, tobramycin, geneticin) promoted flipping of adenine bases (A1492/A1493) in the ribosomal A-site, unlike streptomycin and hygromycin B.

Conclusions:

  • The ability of aminoglycosides to induce initiation shifts in trans-translation is linked to their structural similarity and their capacity to alter ribosomal A-site conformation.
  • Specific structural features, particularly rings I and II, are critical for this effect.
  • These findings provide insight into the mechanism of action of aminoglycosides and their interaction with the bacterial ribosome during trans-translation.

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