Antimicrobial Resistance: Evolutionary Implications of Dual Selection by Bacteriophages and Metal-Based Antimicrobials

Antimicrobial resistance (AMR) represents a critical global health challenge in the 21st century, with drug-resistant infections accounting for approximately 4.95 million deaths annually; moreover, forecasts suggest a significant increase in this toll by 2050. Traditional approaches to antibiotic development have demonstrated an inability to keep pace with bacterial evolution. Consequently, there has been a resurgence of scientific interest in alternative therapeutic strategies, specifically bacteriophage therapy and metal-based antimicrobials. This narrative review examines the molecular processes that help bacteria evolve resistance to both phages and metals, a topic often studied separately. It encompasses receptor modification, CRISPR–Cas adaptive immunity, abortive infection systems, efflux pump evolution, the rewiring of regulatory networks, and also examines the impact of dual selection on these mechanisms. We investigate the complex, combined evolutionary effects of exposure to phages and metals, both simultaneously and sequentially. This includes mutations that confer resistance to multiple stressors, the co-selection of resistance traits associated with mobile genetic elements, and the transfer of metal resistance genes between bacteria via phages. The outer membrane, metal transport systems, and efflux pumps are key cellular areas where phages and metals create overlapping and interacting selective pressures. Direct experimental evidence for combined phage–metal selection remains scarce, and we therefore distinguish throughout between direct phage–metal evidence, evidence transferred from phage–antibiotic and metal–antibiotic systems, and mechanistic hypotheses that remain to be tested. Understanding these complex evolutionary dynamics is essential for formulating combination therapeutic approaches that reduce the emergence of resistance, improve antimicrobial effectiveness, and address the growing challenge of multidrug-resistant pathogens in both clinical and environmental settings.