Anti-virulence strategies for Clostridioides difficile infection: advances and roadblocks

Abstract

Clostridioides difficile infection (CDI) is a common healthcare- and antibiotic-associated diarrheal disease. If mis-diagnosed, or incompletely treated, CDI can have serious, indeed fatal, consequences. The clinical and economic burden imposed by CDI is great, and the US Centers for Disease Control and Prevention has named the causative agent, C. difficile (CD), as an Urgent Threat To US healthcare. CDI is also a significant problem in the agriculture industry. Currently, there are no FDA-approved preventives for this disease, and the only approved treatments for both human and veterinary CDI involve antibiotic use, which, ironically, is associated with disease relapse and the threat of burgeoning antibiotic resistance. Research efforts in multiple laboratories have demonstrated that non-toxin factors also play key roles in CDI, and that these are critical for disease. Specifically, key CD adhesins, as well as other surface-displayed factors have been shown to be major contributors to host cell attachment, and as such, represent attractive targets for anti-CD interventions. However, research on anti-virulence approaches has been more limited, primarily due to the lack of genetic tools, and an as-yet nascent (but increasingly growing) appreciation of immunological impacts on CDI. The focus of this review is the conceptualization and development of specific anti-virulence strategies to combat CDI. Multiple laboratories are focused on this effort, and the field is now at an exciting stage with numerous products in development. Herein, however, we focus only on select technologies (Figure 1) that have advanced near, or beyond, pre-clinical testing (not those that are currently in clinical trial), and discuss roadblocks associated with their development and implementation.

The Alternative Sigma Factor SigL Influences Clostridioides difficile Toxin Production, Sporulation, and Cell Surface Properties

“…Clostridioides difficile, an anaerobic, spore-forming, Gram-positive bacillus, is a significant source of healthcare-associated infections (Stewart et al, 2020) . C. difficile infection manifests as a diverse spectrum of diarrheal disease with possible progression toward more serious sequelae including pseudomembranous colitis or fatal toxic megacolon (George et al, 1978;Dudukgian et al, 2009).…”

Clostridioides difficile specific DNA adenine methyltransferase CamA squeezes and flips adenine out of DNA helix

“…In the developed world, C. difficile is one of the leading causes of hospital-acquired infections, often following antibiotic therapy 4 . This pathogen produces endospores, making decontamination difficult 5 , 6 , and it causes deadly infections by producing significant toxins 7 , 8 , and by stabilizing the colon bacterial population (microbiota, or microbiome) in an unhealthy distribution 9 , 10 . The US Centers for Disease Control and Prevention has classified C. difficile infections as being an urgent healthcare risk, associated with substantial morbidity and mortality 11 .…”

The Alternative Sigma Factor SigL Influences Clostridioides difficile Toxin Production, Sporulation, and Cell Surface Properties

“…Clostridioides difficile , an anaerobic, spore-forming, Gram-positive bacillus, is a significant cause of healthcare-associated infections (Stewart et al, 2020 ). C. difficile infection manifests as a diverse spectrum of diarrheal diseases with possible progression toward more serious sequelae, including pseudomembranous colitis or fatal toxic megacolon (George et al, 1978 ; Dudukgian et al, 2009 ).…”