Document Type

Article

Publication Title

Molecular Microbiology

Publication Date

2026

Keywords

aminoglycosides, DNA damage, MDR pathogens, oxidative stress, proteotoxicity, silver

Abstract

The rise of multidrug-resistant (MDR) bacterial pathogens, including uropathogenic Escherichia coli (UPEC), highlights the urgent need for alternative treatment strategies to restore antibiotic efficacy. The silver-ruthenium antimicrobial AGXX exerts potent bactericidal effects through the production of reactive oxygen species (ROS); however, its potential synergy with antibiotics has not been thoroughly investigated. Here, we show that sublethal concentrations of AGXX strongly enhance aminoglycoside-mediated killing across a diverse panel of Gram-negative and Gram-positive MDR clinical isolates, including highly aminoglycoside-resistant strains. Combinational treatments significantly reduced the effective concentrations of gentamicin, tobramycin, kanamycin, and amikacin required to kill bacteria. Mechanistic analyses revealed that AGXX/aminoglycoside co-treatments induce pronounced intracellular ROS accumulation, resulting in an imbalanced proteostasis due to extensive protein aggregation and DNA damage. Scavenging ROS abolished synergistic killing, establishing oxidative imbalance as the primary driver of the synergy between both antimicrobials. We further identified polyphosphate as a key bacterial defense mechanism that mitigates ROS accumulation, proteotoxicity, and genotoxic stress during combinational treatment. Moreover, AGXX–aminoglycoside synergy was preserved in an artificial urine medium and across clinical UPEC isolates, underscoring its relevance to urinary tract infections. Together, these findings position AGXX as a potent aminoglycoside adjuvant that restores antibiotic efficacy through ROS-driven macromolecular damage, supporting its development for combination therapies against MDR bacterial infections.

Funding Source

This work was supported by the NIAID grants 1R15AI194270-01A1 and 1R03AI174033-01A1 (to J.-U. D.). This article was published open access thanks to a transformative agreement between Milner Library and Wiley.

Comments

First published in Molecular Microbiology (2026): https://doi.org/10.1111/mmi.70094

Creative Commons License

Creative Commons Attribution-NonCommercial 4.0 International License
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License

DOI

10.1111/mmi.70094

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