Biology subjects

Oladokun, E. P.

Publications and source records attributed to Oladokun, E. P..

2 recordsLinked to original sources

bioRxiv2025

The Synergy between a Silver-Ruthenium Antimicrobial and aminoglycosides is based on severe macromolecular damage

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(R) 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(R) 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 for bacterial killing. Mechanistic analyses revealed that AGXX(R)/aminoglycoside co-treatment induces pronounced intracellular ROS accumulation, resulting in severe proteotoxic stress, 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 identify polyphosphate as a key bacterial defense mechanism that mitigates ROS accumulation, proteotoxicity, and genotoxic stress during combinational treatment. Moreover, AGXX(R)-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(R) as a potent aminoglycoside adjuvant that restores antibiotic efficacy through ROS-driven macromolecular damage, supporting its development for combination therapies against MDR bacterial infections.

microbiology↗

bioRxiv2025

A Novel Silver-Ruthenium-Based Antimicrobial Kills Gram-Negative Bacteria Through Oxidative Stress-Induced Macromolecular Damage

Amplified by the decline in antibiotic discovery, the rise of antibiotic resistance has become a significant global challenge in infectious disease control. Extraintestinal Escherichia coli (ExPEC), known to be the most common instigators of urinary tract infections (UTIs), represent such global threat. Novel strategies for more efficient treatments are therefore desperately needed. These include silver nanoparticles, which have been used as antimicrobial surface-coatings on catheters to eliminate biofilm-forming uropathogens and reduce the risk of nosocomial infections. AGXX(R) is a promising silver coating that presumably kills bacteria through the generation of reactive oxygen species (ROS) but is more potent than silver. However, neither is AGXX(R)s mode of action fully understood, nor have its effects on Gram-negative bacteria or bacterial response and defense mechanisms towards AGXX(R) been studied in detail. Here, we report that the bactericidal effects of AGXX(R) are primarily based on ROS formation, as supplementation of the media with a ROS scavenger completely abolished AGXX(R)-induced killing. We further show that AGXX(R) impairs the integrity of the bacterial cell envelope and causes substantial protein aggregation and DNA damage already at sublethal concentrations. ExPEC strains appear to be more resistant to the proteotoxic effects of AGXX(R) compared to non-pathogenic E. coli, indicating improved defense capabilities of the uropathogen. Global transcriptomic studies of AGXX(R)-stressed ExPEC revealed a strong oxidative stress response, perturbations in metal homeostasis, as well as the activation of heat shock and DNA damage responses. Finally, we present evidence that ExPEC counter AGXX(R) damage through the production of the chaperone polyphosphate.

microbiology↗