Clostridium difficile phages: still difficult?

Abstract

Phages that infect Clostridium difficile were first isolated for typing purposes in the 1980s, but their use was short lived. However, the rise of C. difficile epidemics over the last decade has triggered a resurgence of interest in using phages to combat this pathogen. Phage therapy is an attractive treatment option for C. difficile infection, however, developing suitable phages is challenging. In this review we summarize the difficulties faced by researchers in this field, and we discuss the solutions and strategies used for the development of C. difficile phages for use as novel therapeutics. Epidemiological data has highlighted the diversity and distribution of C. difficile, and shown that novel strains continue to emerge in clinical settings. In parallel with epidemiological studies, advances in molecular biology have bolstered our understanding of C. difficile biology, and our knowledge of phage–host interactions in other bacterial species. These three fields of biology have therefore paved the way for future work on C. difficile phages to progress and develop. Benefits of using C. difficile phages as therapeutic agents include the fact that they have highly specific interactions with their bacterial hosts. Studies also show that they can reduce bacterial numbers in both in vitro and in vivo systems. Genetic analysis has revealed the genomic diversity among these phages and provided an insight into their taxonomy and evolution. No strictly virulent C. difficile phages have been reported and this contributes to the difficulties with their therapeutic exploitation. Although treatment approaches using the phage-encoded endolysin protein have been explored, the benefits of using “whole-phages” are such that they remain a major research focus. Whilst we don’t envisage working with C. difficile phages will be problem-free, sufficient study should inform future strategies to facilitate their development to combat this problematic pathogen.

Diversity and Evolution in the Genome of Clostridium difficile

“…Phages have coevolved with C. difficile over very long periods of time, and phage infection is an inherent part of the natural history and biology of C. difficile (22,130). Phages are capable of mediating HGT via a process known as transduction, whereby host DNA is packaged into the head particle of a phage and subsequently inserted into the genome of a recipient cell.…”

“…Phages are capable of mediating HGT via a process known as transduction, whereby host DNA is packaged into the head particle of a phage and subsequently inserted into the genome of a recipient cell. Consequently, the acquisition of phages by and their loss from the C. difficile genome are significant genetic events that have impacted host evolution (22,130).…”

“…Phage therapy and treatment with monoclonal antibodies are also active areas of interest (22,23). In up to 20% of fulminant colitis cases, surgical intervention (subtotal colectomy, resection, and/or ileostomy) is required (24).…”

Clostridium difficile infection: Evolution, phylogeny and molecular epidemiology

“…Other more recent alternative therapeutic strategies for CDI include administration of monoclonal antibodies, more new antibiotics, molecular inhibitors e.g. quorum sensing and riboswitch ligands and new probiotics (Gerding, 2012;Hargreaves and Clokie, 2014;Vickers et al, 2016;Zanella Terrier et al, 2014).…”

Clostridium difficile Infection

“…It is possible that specific prophylactic elimination of C. difficile in high-risk groups could reduce the risk of CDI without altering the host microbiota. It is of interest that bacteriocins and viruses (bacteriophages) seem to be able to target C. difficile specifically 232,235,236 .FMT is an excellent potential alternative to antibiotic therapy 206 , but long-term safety, public acceptance and relative lack of standardized donor material are limiting broad application. Steps have been taken to generate standardized formulations of FMT or bacteria 42,149,211,212 .…”