Compounds for the Treatment of Clostridium difficile Infection
Tech ID: 20-062, 17-010
Inventors: Dr. Shahriar Mobashery, Dr. Mayland Chang, Dr. Derong Ding, Dr. Enrico Speri
Date updated: December 15, 2020
Two new antibiotic therapies that selectively and potently target Gram-positive spore-forming C. difficile infections in the large intestine.
Clostridioides difficile (C. difficile or C. diff) is a Gram-positive, anaerobic, spore-forming bacterium. Its production of dormant and antibiotic-impervious spores results in chronic disruption of normal gut flora, debilitating diarrhea, and intestinal infection. C. diff infection (CDI) is considered an urgent health problem as it afflicts approximately 224,000 individuals and kills about 13,000 annually in the US alone. Major challenges for oral chemotherapy of bacterial infections such as CDI are disruption of normal gut flora, the development of resistance, and failure to reduce infection recurrence. The disruption of the normal gut flora due to use of broad-spectrum antibiotics is especially problematic for CDI, because it facilitates the colonization and proliferation of C. diff in the large intestine. The current antibiotics used for CDI are metronidazole (MTZ), fidaxomicin (FDX) and vancomycin (VAN), with FDX and VAN recommended as first-line therapies. FDX is a narrow-spectrum bactericidal antibiotic effective against C. diff, however its use is limited due to its high cost and decreased efficacy against the highly virulent BI/NAP1/027 strain. VAN treatment promotes the growth of VAN-resistant enterococci and has a 25% recurrence. There are no antibiotics that are effective for multiple recurrences. New antibiotics are needed with low oral bioavailability that can achieve high concentrations in the gastrointestinal track.
Researchers at the University of Notre Dame have recently discovered two novel antibiotic therapies that are selective against C. diff. The 17-010 therapy is bactericidal, active against vegetative cells and stationary-phase cells, and inhibits spore germination. The 20-062 therapy is bacteriostatic and targets selectively C. diff. Both compounds inhibit cell-wall biosynthesis and achieve high concentrations in the gut.
• More potent than vancomycin
• More selective - disrupts C. difficile cell-wall biosynthesis without killing normal gut flora.
• Inhibits spore germination
CDI affects 224,000 Americans and kills 13,000 annually.
Discovery of a Potent Picolinamide Antibacterial
Active against Clostridioides difficile.
Structure-Activity Relationship for the Oxadiazole
Class of Antibacterials.
Technology Readiness Status
TRL4 - Lab Validation