Targeting bacterial persistence with bacteriophages: a next-generation antimicrobial strategy

Antibiotic resistance has become a problem of global concern. However, less focus has been placed on scenarios where antibiotics fail to work in the absence of genetic resistance. To survive in hostile conditions, bacteria also use sophisticated defensive strategies, such as constructing protective biofilms, developing specialized dormant persister cells, and entering viable but non-culturable states. These survival mechanisms help bacteria withstand stressors, such as antibiotic treatment and immune responses, leading to persistent infections that conventional therapies struggle to eliminate. Bacteriophages are viruses that naturally prey on bacteria; hence, they offer a promising alternative antibacterial approach by specifically targeting resilient bacterial populations. Therefore, understanding the interactions between phages and bacterial survival mechanisms is crucial for developing innovative therapeutic strategies. Suitably, this review discusses the mechanisms by which phages dismantle biofilms, eliminate persisters, and resuscitate viable but non-culturable cells. Phage-derived enzymes, such as depolymerases and endolysins, enhance biofilm degradation, whereas specific phages induce metabolic reactivation in dormant cells, rendering them more susceptible to treatment. Advancements in phage engineering, including modifications to improve host recognition and antimicrobial potency, have further enhanced the efficacy of phages against bacterial survival strategies. Additionally, combining phages with antibiotics or resuscitation-inducing compounds has shown promising potential for overcoming bacterial persistence. By harnessing these natural predators, phage therapy provides a viable solution for managing antibiotic-resistant infections in clinical, industrial, and environmental settings. Overall, this review highlights the favorable potential of phages as powerful tools against persistent bacterial threats and paves the way for the development of next-generation antimicrobial approaches.