Microbial strains may possess inherent resistance or acquire resistance genes through horizontal gene transfer between bacteria, facilitated by plasmids, phages, or other genetic elements [1]. These resistance genes, often located on plasmids, are expressed through various biochemical mechanisms that protect the bacterial cell [2]. Antibiotic resistance can be categorized into four general mechanisms: target site mutation, efflux pump activity, enzymatic degradation of antibiotics, and reduced membrane permeability [3, 4].

In 2012, the World Health Organization reclassified colistin as critically important for the treatment of multidrug-resistant Gram-negative infections. However, resistance to colistin has recently been reported. Colistin exerts its antibacterial effect by interacting with the negatively charged phosphate groups of lipid A in lipopolysaccharides, leading to cation displacement and cell membrane disruption. Although colistin was first discovered in 1949, plasmid-mediated resistance to colistin in E. coli isolates was identified in 2015 [5]. Colistin and carbapenems were considered the last line of defense against Gram-negative bacteria [6]. However, it is estimated that approximately 50% of prescribed antibiotics are unnecessary or ineffective [7].

Every living organism has its own defense mechanisms to protect against attacks from other organisms, ensuring their survival. When bacteria are attacked by phages, they activate one or more of their defense systems to counter the phages, allowing the bacterial cell to survive the infection and continue to reproduce normally [8]. It is well established that bacteria can resist phage infections by modifying or evolving their surface receptors [9] or by targeting the phage nucleic acids [10]. Antibiotic-resistant opportunistic microorganisms pose a significant risk, particularly to individuals with weakened immune systems or those who are immunocompromised in hospital settings. Phage therapy has the potential to address the major challenges faced in modern medicine [11]. However, despite its promise as a novel approach to combating bacterial infections, the widespread adoption of phage therapy in clinical practice will require substantial advancements. This is due to the current lack of robust evidence supporting the use of phages in human medicine, as well as growing concerns about their stability, quality, and safety.

In this review, we aim to elucidate the various barriers that phages face within biological systems by providing an in-depth analysis of phage pharmacokinetics. We also examine bacterial immune systems and the selective pressures they impose on phages through their interactions. By understanding these dynamics, we can better assess the potential success of phage therapy in future clinical applications. The review concludes with critical insights and clarifications that are essential for advancing research and optimizing the therapeutic use of phages.