4'-O-substitutions determine selectivity of aminoglycoside antibiotics

Nat Commun. 2014;5:3112. doi: 10.1038/ncomms4112.

Abstract

Clinical use of 2-deoxystreptamine aminoglycoside antibiotics, which target the bacterial ribosome, is compromised by adverse effects related to limited drug selectivity. Here we present a series of 4',6'-O-acetal and 4'-O-ether modifications on glucopyranosyl ring I of aminoglycosides. Chemical modifications were guided by measuring interactions between the compounds synthesized and ribosomes harbouring single point mutations in the drug-binding site, resulting in aminoglycosides that interact poorly with the drug-binding pocket of eukaryotic mitochondrial or cytosolic ribosomes. Yet, these compounds largely retain their inhibitory activity for bacterial ribosomes and show antibacterial activity. Our data indicate that 4'-O-substituted aminoglycosides possess increased selectivity towards bacterial ribosomes and little activity for any of the human drug-binding pockets.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aminoglycosides / chemistry*
  • Aminoglycosides / pharmacology*
  • Aminoglycosides / therapeutic use
  • Animals
  • Anti-Bacterial Agents / pharmacology*
  • Anti-Bacterial Agents / therapeutic use
  • Base Sequence
  • Cell-Free System
  • Crystallography, X-Ray
  • Disease Models, Animal
  • Drug Interactions
  • Escherichia coli / drug effects
  • Escherichia coli / isolation & purification
  • Humans
  • Inhibitory Concentration 50
  • Male
  • Mice
  • Microbial Sensitivity Tests
  • Molecular Sequence Data
  • Mycobacterium smegmatis / drug effects
  • Nucleic Acid Conformation
  • Protein Biosynthesis / drug effects
  • RNA, Ribosomal, 16S / chemistry
  • RNA, Ribosomal, 16S / genetics
  • Ribosomes / metabolism
  • Sepsis / drug therapy
  • Staphylococcus aureus / drug effects

Substances

  • Aminoglycosides
  • Anti-Bacterial Agents
  • RNA, Ribosomal, 16S

Associated data

  • PDB/4B3M
  • PDB/4B3R
  • PDB/4B3S
  • PDB/4B3T