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After decades of widespread usage, the resistance to antibiotics has gradually emerged as a global public health problem. Phage therapy, which uses viruses that infect bacteria as an antibacterial agent, is an attractive alternative to traditional antibiotics. As a result, phage therapy is receiving renewed attention. It is worth noting that the evolution of phage resistance is one of the pivotal issues in phage therapies, which may hinder favorable therapeutic outcomes. On the other hand, it was reported that bacterial mutations conferring phage resistance may lead to fitness expenses for resistant bacteria, which in turn may benefit the host. Therefore, it is necessary to develop methods to monitor the resistance.
Resistance to phages can arise through diverse pathways. Receptor modifications that prevent phage adsorption due to point mutations in specific genes or variation in its expression are the most prevalent. In addition, bacteria may also activate restriction modification systems that are responsible for the destruction of invading foreign DNA. Notably, a strategy to inhibit phage DNA replication has been reported in phage-resistant bacteria. Furthermore, bacteria carry a wide range of heterologous proteins that provide resistance by aborting phage infection. Typically, these abortive infection (Abi) systems target critical steps of phage proliferation, and these Abi systems also result in the death of infected cells.
Fig.1 Different strategies used by bacteria to block phage adsorption. (Labrie, 2010)
Phage cocktails play an important role in preventing or combating phage resistance between targets. The main purpose of adding various phages with different host range specificities to the cocktail is to increase its effectiveness. Phage cocktails consisting of phages with different mechanisms of action may increase the activity spectrum of the formulation and reduce the likelihood of developing resistance. Taken together, phage cocktails provide a promising approach to empirical therapy.
An approach to combating phage resistance during phage therapy is to replace the phage to which the patient isolated has developed resistance with an active phage. Large collections of bacteriophages are used to formulate personalized therapies. This approach requires periodic susceptibility testing of phages corresponding to the causative pathogen and other available phages that can be rapidly applied when needed. Thus, phage replacement represents a tailored approach to phage therapy.
Phages have been used in combination with a variety of antibacterial agents and have made great strides. A crucial goal of combination therapy is to minimize the expansion of the resistant selection population in the presence of a therapeutic agent. Therefore, combination therapy offers a potentially effective strategy for resistance.
One of the main features of phages as therapeutics is that phages can evolve their strategies to combat bacterial resistance. By pre-adapting a phage to a bacterial host, the phage will experience how the host evolved resistance and will evolve reciprocally. Phage training aims to harness the evolutionary abilities of phages to create more effective phage therapies.
Fig.2 Model of the impact of phage training on the ability of phage λ to suppress E. coli growth. (Borges, 2021)
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