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G1405 Ribosomal Methyltransferase-Driven Antibacterial Resistance Affects the 4,5-Disubstituted-2-deoxystreptamine

Sven N Hobbie1, Andrea Vasella2, Erik C Böttger1

  • 1Institute of Medical Microbiology, Universität Zürich, Gloriastrasse 30, Zürich CH-8006, Switzerland.

JACS Au
|February 27, 2026
PubMed

Insights

Modified aminoglycosides (AGAs) can be affected by ribosomal methyltransferases, contrary to previous beliefs. Drug modifications and methylation can reduce antibacterial activity, impacting future antibiotic discovery.

Area of Science:

  • Microbiology
  • Medicinal Chemistry
  • Molecular Biology

Background:

  • Aminoglycosides (AGAs) are antibiotics targeting bacterial ribosomes.
  • 4,5-disubstituted-2-deoxystreptamine (DOS) AGAs and apramycin were thought resistant to ribosomal methyltransferase (RMTase)-mediated G1405 N7 methylation.
  • This resistance mechanism is a key factor in aminoglycoside resistance.

Purpose of the Study:

  • To investigate the impact of modifications on 4,5-DOS AGAs and apramycin activity in the presence of RMTases.
  • To challenge the established understanding of resistance mechanisms for these AGA classes.
  • To guide future antibiotic discovery efforts.

Main Methods:

  • Synthesis of modified 4,5-DOS AGAs.
  • Determination of minimum inhibitory concentrations (MICs).
  • Assessment of susceptibility to G1405 N7 ribosomal methyltransferases.

Main Results:

  • Contrary to common perception, modified 4,5-DOS AGAs showed reduced activity influenced by G1405 N7 RMTases.
  • Combined effects of drug modification and G1405 N7 methylation can decrease antibacterial efficacy.
  • Modifications enhancing drug-ribosome binding affinity, like in propylamycin and apralogs, confer resistance to RMTase activity.

Conclusions:

  • The perceived resistance of 4,5-DOS AGAs and apramycin to RMTase-mediated G1405 N7 methylation is not absolute, especially with drug modifications.
  • Drug modifications can create synergistic effects with methylation, leading to reduced antibiotic activity.
  • Future antibiotic discovery should consider these drug-ribosome-RMTase interactions for designing effective compounds.
Keywords:
aminoglycoside antibioticsantibacterial resistanceapramycinmultidrug resistanceribosomal methyltransferases

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