Bacterial Resistance to Phage Therapy: Mechanisms and Strategies to Overcome It Publisher



Karamlou S ; Aghajani E ; Familsamavati M ; Azad NF ; Arayesh S ; Mohsenipour Z
Source: Current Molecular Pharmacology Published:2025

Abstract

The escalating global threat of antibiotic-resistant bacterial pathogens has prompted a critical search for alternative therapeutic strategies, among which bacteriophage (phage) therapy has emerged as a promising, targeted antimicrobial approach. However, there is a challenge in the development of phage therapy, which is the rapid resistance of pathogens to specific phages. Therefore, this review aims to comprehensively examine the molecular mechanisms of bacterial resistance to phage infection and explore the strategies designed to overcome this challenge. At first, we focused on bacterial defense mechanisms against phage infection, including surface receptor modification, restriction-modification systems, CRISPR-Cas immunity, and biofilm formation. We also compared phage resistance with antibiotic resistance and discusses strategies to mitigate resistance, such as phage cocktails, genetic engineering, and combination therapies. Bacterial defenses not only impose heavy costs on bacteria, but also, pose a significant challenge to phage therapy's long-term success. The co-evolutionary arms race between phages and bacteria drives rapid adaptation and diversification. Understanding this dynamic is crucial for developing robust therapeutic protocols. Strategies such as using engineered phages, phage cocktails, and combining phages with antibiotics can effectively counteract bacterial resistance. Bacterial resistance to phages is a complex and formidable challenge, but the field's adaptive strategies, grounded in evolutionary biology and synthetic biology, offer promising solutions. Therefore, the combination of integrated molecular, clinical, and regulatory innovations is essential to advance phage therapy as a sustainable solution against multidrug-resistant infections. © 2025 FAR Publishing Limited.