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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, IL.

Biorxiv : the Preprint Server for Biology
|February 9, 2026
PubMed

Insights

The silver-ruthenium antimicrobial AGXX enhances aminoglycoside antibiotics, restoring their efficacy against multidrug-resistant bacteria. This combination therapy combats infections by increasing reactive oxygen species (ROS) and damaging bacterial cells.

Area of Science:

  • Antimicrobial resistance
  • Nanotechnology in medicine
  • Bacterial pathogenesis

Background:

  • Multidrug-resistant (MDR) bacterial infections pose a significant global health threat.
  • Uropathogenic Escherichia coli (UPEC) is a common cause of urinary tract infections (UTIs).
  • Novel strategies are needed to restore the efficacy of existing antibiotics.

Purpose of the Study:

  • To investigate the synergistic potential of the silver-ruthenium antimicrobial AGXX® with aminoglycoside antibiotics.
  • To explore the mechanisms underlying any observed synergy.
  • To assess the efficacy of AGXX®-aminoglycoside combinations against MDR clinical isolates, including UPEC.

Main Methods:

  • Testing AGXX® in combination with gentamicin, tobramycin, kanamycin, and amikacin against MDR Gram-negative and Gram-positive bacteria.
  • Measuring intracellular reactive oxygen species (ROS) levels, proteotoxic stress, protein aggregation, and DNA damage.
  • Evaluating the role of ROS in synergistic killing by using ROS scavengers.
  • Investigating bacterial defense mechanisms, including polyphosphate.
  • Assessing efficacy in an artificial urine medium and against clinical UPEC isolates.

Main Results:

  • Sublethal AGXX® concentrations significantly potentiated aminoglycoside-mediated bacterial killing.
  • Combinations reduced the effective concentrations of multiple aminoglycosides against resistant strains.
  • AGXX®/aminoglycoside co-treatment induced substantial intracellular ROS accumulation, proteotoxic stress, and DNA damage.
  • ROS scavenging abolished the synergistic killing effect.
  • Polyphosphate was identified as a bacterial defense mechanism against ROS-induced 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.
  • AGXX®-aminoglycoside combination therapy shows promise for treating MDR bacterial infections, particularly UTIs.
  • Further development of AGXX® for combination therapies is warranted.

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