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The Synergy Between a Silver-Ruthenium Antimicrobial and Aminoglycosides Is Based on Severe Macromolecular Damage

Emmanuel P Oladokun1, Gracious Y Donkor1, Julius K Narh1

  • 1School of Biological Sciences, Illinois State University, Normal, Illinois, USA.

Molecular Microbiology
|July 11, 2026
PubMed

Insights

The silver-ruthenium antimicrobial AGXX boosts aminoglycoside antibiotic effectiveness against multidrug-resistant bacteria by increasing reactive oxygen species (ROS) and damaging bacterial cells. This combination therapy shows promise for treating resistant infections, including urinary tract infections.

Area of Science:

  • Antimicrobial resistance
  • Nanotechnology in medicine
  • Bacterial pathogenesis

Background:

  • Multidrug-resistant (MDR) bacterial infections, particularly uropathogenic Escherichia coli (UPEC), necessitate novel therapeutic strategies.
  • The silver-ruthenium antimicrobial AGXX demonstrates bactericidal activity via reactive oxygen species (ROS) production.
  • The synergistic potential of AGXX with existing antibiotics remains underexplored.

Purpose of the Study:

  • To investigate the synergistic effects of AGXX combined with aminoglycoside antibiotics against MDR bacterial isolates.
  • To elucidate the underlying mechanisms driving the observed synergy.
  • To assess the therapeutic relevance of AGXX-aminoglycoside combinations for urinary tract infections.

Main Methods:

  • Testing AGXX/aminoglycoside combinations against diverse Gram-negative and Gram-positive MDR clinical isolates.
  • Quantifying intracellular ROS accumulation and assessing proteostasis and DNA damage.
  • Evaluating the role of ROS scavenging in abrogating synergistic killing.
  • Investigating the role of bacterial polyphosphate in mediating resistance.
  • Assessing efficacy in an artificial urine medium and against clinical UPEC isolates.

Main Results:

  • Sublethal AGXX concentrations significantly enhanced aminoglycoside killing of MDR bacteria, including highly resistant strains.
  • Combinations reduced effective antibiotic concentrations for gentamicin, tobramycin, kanamycin, and amikacin.
  • AGXX/aminoglycoside co-treatments induced substantial intracellular ROS, leading to protein aggregation and DNA damage.
  • ROS scavenging abolished the synergistic effect, confirming oxidative imbalance as the key driver.
  • Bacterial polyphosphate was identified as a defense mechanism against ROS and associated damage.
  • Synergy was maintained in artificial urine and against clinical UPEC isolates.

Conclusions:

  • AGXX acts as a potent adjuvant, restoring aminoglycoside efficacy against MDR bacteria.
  • The synergy is driven by ROS-induced macromolecular damage, overcoming bacterial defense mechanisms.
  • This combination therapy holds promise for treating challenging MDR bacterial infections, including UTIs.
Keywords:
DNA damageMDR pathogensaminoglycosidesoxidative stressproteotoxicitysilver

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