The long and sinuous road to phage-based therapy of Clostridioides difficile infections

Abstract

With the antibiotic crisis and the rise in antimicrobial resistance worldwide, new therapeutic alternatives are urgently needed. Phage therapy represents one of the most promising alternatives but for some pathogens, such as Clostridioides difficile, important challenges are being faced. The perspective of phage therapy to treat C. difficile infections is complicated by the fact that no strictly lytic phages have been identified so far, and current temperate phages generally have a narrow host range. C. difficile also harbors multiple antiphage mechanisms, and the bacterial genome is often a host of one or multiple prophages that can interfere with lytic phage infection. Nevertheless, due to recent advances in phage host receptor recognition and improvements in genetic tools to manipulate phage genomes, it is now conceivable to genetically engineer C. difficile phages to make them suitable for phage therapy. Other phage-based alternatives such as phage endolysins and phage tail-like bacteriocins (avidocins) are also being investigated but these approaches also have their own limitations and challenges. Last but not least, C. difficile produces spores that are resistant to phage attacks and all current antibiotics, and this complicates therapeutic interventions. This mini-review gives a brief historical overview of phage work that has been carried out in C. difficile, presents recent advances in the field, and addresses the most important challenges that are being faced, with potential solutions.

Prophage Carriage and Genetic Diversity within Environmental Isolates of Clostridioides difficile

“…In total, 372, 633, and 37 intact, incomplete, and questionable prophages, respectively, were predicated (Figure 1A, Table S1). One, two and ten isolates contained the highest numbers of predicated prophages (12,11, and 10 prophages, respectively), while other isolates hosted between four and nine prophages (Table S1). A total of 20 different intact prophages were identified, ranging between one and six per isolate.…”

“…Phages of the Siphoviridae family have long, flexible, and non-contractile tails [ 8 ]. The natural resistance of C. difficile to a wide range of antibiotics has led researchers to investigate the use of phage therapy to treat CDI [ 9 , 10 , 11 , 12 ]. However, prophage presence or absence and impact on C. difficile biology and lifestyle is still poorly understood due to a lack of knowledge about the genetic background of the host strains.…”

Therapies from Thiopeptides

“…Vancomycin and fidaxomicin are the only two antibacterials currently available to treat such infections. However, they are associated with recurrence rates of 15-30% and display much reduced efficacy against the emerging hypervirulent strain, C. difficile ribotype 027 [44]. There is thus an unmet medical need for new agents that are active against new strains and reduce recurrence rates.…”