Novel avenues forClostridium difficileinfection drug discovery

Abstract

Beyond the development of new antibiotics, virulence-targeting factors or phage cocktails seem promising strategies, which could replace antibiotics avoiding the emergence of resistant strains and the onset of C. difficile infection (CDI). Until broad-spectrum antimicrobials will be in use, C. difficile-specific lytic phages could help to prevent CDI by eliminating C. difficile in patients and in the hospital staff, and for the prevention and treatment of recurrences. Phage therapy is not currently available in Western countries, but, in our opinion, it should have a new chance. Fecal therapy is emerging as a very effective and readily available treatment for recurrences. The shift is from a standardized, drug-based antibacterial therapy toward the forthcoming less expensive and nonpatentable procedures of a more personalized medicine. This will imply profound changes affecting both patient-physician interactions and the current profit-oriented approach to the pharmacologic therapy of infections.

‘Get in Early’; Biofilm and Wax Moth (Galleria mellonella) Models Reveal New Insights into the Therapeutic Potential of Clostridium difficile Bacteriophages

“…A limiting factor to the control of the disease is the lack of treatment options (Zucca et al, 2013; Hargreaves and Clokie, 2014). C. difficile produces spores and biofilms that significantly contribute to its virulence by enabling persistence and proliferation in the environment and gut, and resistance to antimicrobial and cleaning agents (Akerlund et al, 2008; Burns et al, 2011; Burns and Minton, 2011; Dawson et al, 2012; Đapa et al, 2013).…”

“…C. difficile infections (CDI) are becoming increasingly severe due to limited treatment options and the emergence of pathogenic ribotypes (Freeman et al, 2010; Zucca et al, 2013). Complications of the disease can also arise from antibiotic resistance, leading to relapse, increased health care-associated costs and death in 10% cases (Wiegand et al, 2012; Lessa et al, 2015; Vindigni and Surawicz, 2015).…”

“…In addition to medical uses, their safety, specificity and ability to replicate in situ has meant that phages both can and are currently used in the food industry as alternatives to antibiotics and as decontamination agents (EBI Food Safety, 2007; Hagens and Loessner, 2010; Kumari et al, 2011). Although several C. difficile phages have been characterized, few studies have focused on their potential applications for the treatment of CDI (Zucca et al, 2013; Hargreaves and Clokie, 2014; Nale et al, 2016). Most therapeutic studies have investigated single phages, and reported the isolation of resistant and lysogenic clones (Ramesh et al, 1999; Govind et al, 2009; Meader et al, 2010, 2013; Nale et al, 2016).…”

Clostridium difficile phages: still difficult?

“…These include new antibiotics, antimicrobial peptides, bacteriocins, molecular inhibitors such as quorum sensing and riboswitch ligands, toxin targeting molecules such as antibodies, and the use of other bacteria as probiotics or fecal transplants. These approaches are at various stages of development and are discussed in a recent review and are not considered further here [see review by (Zucca et al, 2013)].…”

Clostridium difficile colonization and antibiotics response in PolyFermS continuous model mimicking elderly intestinal fermentation

“…Clostridium difficile (CD) was first identified in the 1970s as the causative agent of antibiotic-associated pseudomembranous colitis and is now the leading cause of hospital-acquired diarrhea [1]. CD is a gram-positive anaerobic bacterium harboring several virulence factors such as the ability to form spores and produce toxins [2].…”