CRS3123 vs Vancomycin Treatment of CDI Phase II Clinical Trial
CRS3123 is a novel narrow-spectrum antibiotic that inhibits the methionyl-tRNA synthetase of Clostridioides difficile (CdMetRS). Safety and efficacy of CRS3123 for treatment of C. difficile infection (CDI) were recently demonstrated in a Phase II trial, with high clinical cure rates and lower recurrence compared to vancomycin. CRS3123 is highly selective for Type 1 MetRS, which has a limited phylogenetic distribution among gut bacteria compared to Type 2 MetRS. We defined Type 1-specific features of CRS3123 target binding, including cooperativity with ATP and a pronounced induced fit compared to apo CdMetRS. To examine how predicted taxonomic susceptibility may shape microbiome responses in vivo and relate to observed clinical trends, we analyzed the fecal microbiome, metabolome, and soluble immune factors from trial samples. Both 200 mg and 400 mg BID doses of CRS3123 caused less disruption of the commensal microbiome compared to vancomycin (125 QID), with less compositional deviation from external healthy controls. CRS3123 preserved Bifidobacterium and Bacteroides while effectively clearing C. difficile and vancomycin-resistant enterococci (VRE) and reducing fecal inflammatory markers. In contrast, vancomycin shifted communities toward Enterobacteriaceae. Shotgun metagenomics and targeted metabolomics showed that CRS3123- treated microbiomes retained the capacity to produce lithocholic acid, a secondary bile acid that suppresses C. difficile, whereas vancomycin promoted accumulation of conjugated primary bile acids that enhance germination. Overall, CRS3123 matches vancomycin in CDI resolution while better preserving key taxa and metabolites that may reduce CDI recurrence.
CRS3123 is a novel narrow-spectrum antibiotic that inhibits the methionyl-tRNA synthetase of Clostridioides difficile (CdMetRS). Safety and efficacy of CRS3123 for treatment of C. difficile infection (CDI) were recently demonstrated in a Phase II trial, with high clinical cure rates and lower recurrence compared to vancomycin. CRS3123 is highly selective for Type 1 MetRS, which has a limited phylogenetic distribution among gut bacteria compared to Type 2 MetRS. We defined Type 1-specific features of CRS3123 target binding, including cooperativity with ATP and a pronounced induced fit compared to apo CdMetRS. To examine how predicted taxonomic susceptibility may shape microbiome responses in vivo and relate to observed clinical trends, we analyzed the fecal microbiome, metabolome, and soluble immune factors from trial samples. Both 200 mg and 400 mg BID doses of CRS3123 caused less disruption of the commensal microbiome compared to vancomycin (125 QID), with less compositional deviation from external healthy controls. CRS3123 preserved Bifidobacterium and Bacteroides while effectively clearing C. difficile and vancomycin-resistant enterococci (VRE) and reducing fecal inflammatory markers. In contrast, vancomycin shifted communities toward Enterobacteriaceae. Shotgun metagenomics and targeted metabolomics showed that CRS3123- treated microbiomes retained the capacity to produce lithocholic acid, a secondary bile acid that suppresses C. difficile, whereas vancomycin promoted accumulation of conjugated primary bile acids that enhance germination. Overall, CRS3123 matches vancomycin in CDI resolution while better preserving key taxa and metabolites that may reduce CDI recurrence.
University of Colorado Anschutz