Battling Enteropathogenic Clostridia: Phage Therapy for Clostridioides difficile and Clostridium perfringens

Abstract

The pathogenic Clostridioides difficile and Clostridium perfringens are responsible for many health care-associated infections as well as systemic and enteric diseases. Therefore, they represent a major health threat to both humans and animals. Concerns regarding increasing antibiotic resistance (related to C. difficile and C. perfringens) have caused a surge in the pursual of novel strategies that effectively combat pathogenic infections, including those caused by both pathogenic species. The ban on antibiotic growth promoters in the poultry industry has added to the urgency of finding novel antimicrobial therapeutics for C. perfringens. These efforts have resulted in various therapeutics, of which bacteriophages (in short, phages) show much promise, as evidenced by the Eliava Phage Therapy Center in Tbilisi, Georgia (https://eptc.ge/). Bacteriophages are a type of virus that infect bacteria. In this review, the (clinical) impact of clostridium infections in intestinal diseases is recapitulated, followed by an analysis of the current knowledge and applicability of bacteriophages and phage-derived endolysins in this disease indication. Limitations of phage and phage endolysin therapy were identified and require considerations. These include phage stability in the gastrointestinal tract, influence on gut microbiota structure/function, phage resistance development, limited host range for specific pathogenic strains, phage involvement in horizontal gene transfer, and—for phage endolysins—endolysin resistance, -safety, and -immunogenicity. Methods to optimize features of these therapeutic modalities, such as mutagenesis and fusion proteins, are also addressed. The future success of phage and endolysin therapies require reliable clinical trial data for phage(-derived) products. Meanwhile, additional research efforts are essential to expand the potential of exploiting phages and their endolysins for mitigating the severe diseases caused by C. difficile and C. perfringens.

Clostridioides difficile S-Layer Protein A (SlpA) Serves as a General Phage Receptor

“…Phage therapy has gained interest in recent years, and treatment of C. difficile infections with therapeutic phages could have huge advantages over currently available antibiotics. Therefore, phage therapy has been viewed as a potential alternative to fight C. difficile infections ( 3 , 4 ). However, it is currently constrained by the fact that all phages known to infect C. difficile are temperate, and thus, capable of lysogeny ( 7 ).…”

“…Since broad-spectrum antibiotics often lead to collateral damage, more targeted therapeutics are needed, especially in the context of gastrointestinal infections ( 2 ). Clostridioides difficile is one of the Gram-positive pathogens for which phage therapy has been proposed as a potential therapeutic alternative ( 3 , 4 ). C. difficile is the main cause of antibiotic-associated diarrhea in hospitals, and therapeutic solutions are limited, particularly in the context of recurrent infections ( 2 ).…”

The Clostridioides difficile S-Layer Protein A (SlpA) serves as a general phage receptor

“…Phage therapy has gained interest in recent years and treatment of C. difficile infections with therapeutic phages could have huge advantages over currently available antibiotics. Therefore, phage therapy has been viewed as a potential alternative to fight C. difficile infections (3, 4). However, it is currently constrained by the fact that all phages known to infect C. difficile are temperate, and thus, capable of lysogeny (6).…”

“…Since broad spectrum antibiotics often lead to collateral damages, more targeted therapeutics are needed, especially in the context of gastrointestinal infections (2). Clostridioides difficile is one of the Gram-positive pathogens for which phage therapy has been proposed as a potential therapeutic alternative (3, 4). C. difficile is the main cause of antibiotic-associated diarrhea in hospitals and therapeutic solutions are limited, particularly in the context of recurrent infections (2).…”

Alternatives Therapeutic Approaches to Conventional Antibiotics: Advantages, Limitations and Potential Application in Medicine

“…Thus, phage therapy has shown to be an interesting alternative in the fight against multi-drug resistant bacteria [ 73 ]. Phages or bacteriophages are lytic viruses that exclusively and specifically infect bacterial species, showing bactericidal effects against both Gram-positive and Gram-negative bacteria [ 74 , 75 ]. In contrast, some tend to be specific to a particular species or strain of bacteria [ 76 ].…”