Current Knowledge and Perspectives of Phage Therapy for Combating Refractory Wound Infections

Abstract

Wound infection is one of the most important factors affecting wound healing, so its effective control is critical to promote the process of wound healing. However, with the increasing prevalence of multi-drug-resistant (MDR) bacterial strains, the prevention and treatment of wound infections are now more challenging, imposing heavy medical and financial burdens on patients. Furthermore, the diminishing effectiveness of conventional antimicrobials and the declining research on new antibiotics necessitate the urgent exploration of alternative treatments for wound infections. Recently, phage therapy has been revitalized as a promising strategy to address the challenges posed by bacterial infections in the era of antibiotic resistance. The use of phage therapy in treating infectious diseases has demonstrated positive results. This review provides an overview of the mechanisms, characteristics, and delivery methods of phage therapy for combating pathogenic bacteria. Then, we focus on the clinical application of various phage therapies in managing refractory wound infections, such as diabetic foot infections, as well as traumatic, surgical, and burn wound infections. Additionally, an analysis of the potential obstacles and challenges of phage therapy in clinical practice is presented, along with corresponding strategies for addressing these issues. This review serves to enhance our understanding of phage therapy and provides innovative avenues for addressing refractory infections in wound healing.

Keywords: MDR; alternative treatments; antibiotic resistance; phage therapy; wound healing; wound infection.

Figure 1

Four phases of wound healing: The initial stage of wound healing, known as hemostasis, involves platelet aggregation to prevent hemorrhage and the formation of an early fibrin clot. Following this, the inflammatory phase is essential for clearing debris and preventing infection, with the recruitment of neutrophils and monocytes that subsequently differentiate into tissue macrophages. The proliferation stage encompasses angiogenesis to restore blood vessels and the replacement of the provisional fibrin clot with granulation tissue by fibroblasts. Ultimately, fibroblasts play a key role in remodeling the extracellular matrix, facilitating the restoration of the skin barrier. Figure made with Figdraw.

Figure 2

Schematic diagram of phage antimicrobial therapy: Phages and their products provide routes that could lead to the creation of novel antimicrobial strategies. (A) Phages can irreversibly recognize and bind to particular bacterial pathogens and induce cell lysis during replication. (B) Phages can disrupt biofilms by selectively targeting bacteria within these complex structures, and they can also produce depolymerases, lysozymes, and lytic enzymes to disperse biofilms and induce cell lysis. (C) Some phage-derived recombinant products, such as enzymes, peptides, and small molecules, can be used to target specific bacteria and induce cell lysis. (D) Phages can sensitize antibiotic-resistant bacteria, and this strategy can be combined with antibiotic treatment. For example, bioengineered phages can introduce dominant antibiotic-sensitive genes into drug-resistant hosts. Subsequently, the expressed drug-sensitive enzyme can bind to antibiotics and reverse/cancel antibiotic resistance. Figure made with Figdraw.

Figure 3

Novel phage delivery systems to infectious wounds. Figure made with Figdraw.

Figure 4

Schematic diagram of phage engineering: Phages have traditionally been characterized as exhibiting high specificity towards their host bacteria, primarily attributed to the specific interactions between adhesion proteins and their corresponding receptors. Phages consist of an outer shell and an internal genome. Through genetic manipulation, phages can be engineered to express specific adhesion proteins in their tail fibers. These modified phages are capable of binding to a wider range of pathogenic bacteria and demonstrating a broader spectrum of antibacterial activity. Figure made with Figdraw.