An Engineered Synthetic Biologic Protects Against Clostridium difficile Infection

Area of Science:

• Synthetic biology
• Microbiology
• Gastroenterology

Background:

• Clostridium difficile infection (CDI) causes significant morbidity and mortality.
• Current antibiotic treatments for CDI are associated with relapse and drug resistance.
• Non-toxin virulence factors, such as Surface Layer Protein A (SlpA), are critical for CDI pathogenesis.

Purpose of the Study:

• To engineer synthetic biologic agents (Syn-LAB 2.0 and Syn-LAB 2.1) for treating CDI.
• To evaluate the efficacy of these agents as non-antibiotic interventions for CDI.

Main Methods:

• Engineered lactic acid bacteria to express a host-cell binding fragment of C. difficile SlpA.
• Incorporated conditional suicide plasmids and engineered biocontrol for antibiotic-free application.
• Assessed agent properties in vitro (epithelial barrier function) and in vivo (animal models: hamsters, piglets).

Main Results:

• Syn-LAB agents robustly displayed the SlpA chimera and potentiated intestinal epithelial barrier function.
• Agents were safe, tolerable, and colonizing in animal models.
• Syn-LAB combination therapy delayed or prevented death in infected hamsters and ameliorated diarrhea in piglets.

Conclusions:

• Engineered synthetic biologics (Syn-LAB 2.0 and 2.1) demonstrate potential as novel, non-antibiotic treatments for CDI.
• These agents effectively target C. difficile colonization and virulence mechanisms.
• Further investigation is warranted for clinical application in managing CDI.