Bacteriophage-based antibiotic resistant bacteria control in wastewater treatment: advances and prospects

Wastewater treatment plants (WWTPs) are critical hotspots for antibiotic resistance dissemination due to residual antibiotics promoting the proliferation of antibiotic-resistant bacteria (ARB) and antibiotic-resistance genes (ARGs). While conventional disinfection methods (e.g., chlorination, UV irradiation) are widely employed, they often fail to simultaneously inactivate ARB and degrade both intracellular antibiotic-resistance genes (iARGs) and extracellular antibiotic-resistance genes (eARGs), while potentially generating toxic by-products. Bacteriophages (phages) offer a promising eco-friendly alternative, applicable during biological treatment or pre-disinfection. They can specifically target pathogenic or ARB strains without disrupting wastewater biological processes, and notably, ARGs released via phage-mediated ARB lysis are more susceptible to subsequent disinfection, lowering dissemination risks. To illustrate the growing research interest in this field, a statistical analysis of the literature was conducted based on 2377 articles retrieved from the Web of Science database (2015-2025), revealing publication trends in research on phage-mediated control of ARB and ARGs in WWTPs. More importantly, this review summarizes the mechanisms and applications of lytic and lysogenic (temperate) phages for ARB control in wastewater, analyzing key challenges hindering phage application including bacterial anti-phage defenses (e.g., CRISPR-Cas systems, biofilm shielding) and adverse wastewater conditions (e.g., pH fluctuations, particulate adsorption), as well as major application risks such as phage-mediated ARGs transduction. Corresponding mitigation strategies are discussed, including phage cocktails (to expand host range), genetic engineering (to boost lytic activity), and targeted delivery systems (e.g., magnetic nanoparticles). Furthermore, extending beyond host-phage interactions, this review evaluates engineering compatibility, offering novel perspectives to bridge the gap between biological potential and practical application.