Experimental glycopeptide antibiotic EVG7 prevents recurrent Clostridioides difficile infection by sparing members of the Lachnospiraceae family

Oral vancomycin has a long history as the first-line treatment for Clostridioides difficile infection (CDI), but its use is associated with high relapse rates. Antibiotics that more selectively target C. difficile while sparing protective commensal gut bacteria, have the potential to prevent recurrent CDI (rCDI). Here, we investigate the experimental glycopeptide antibiotic, EVG7, in the context of rCDI. In vitro susceptibility assays reveal that clinical C. difficile isolates are up to 16-times more sensitive to EVG7 (MIC = 0.063–0.25 mg/L) compared to vancomycin (MIC = 0.5–2 mg/L). In a validated mouse model of rCDI in male mice, low dose oral EVG7 (0.04 mg/mL in drinking water) more effectively treats primary CDI and prevents recurrence, outperforming a 10-fold higher dose of vancomycin. Subsequent microbiome analysis and in vitro susceptibility testing reveal that EVG7 preserves Lachnospiraceae, a family of commensal bacteria associated with protection against C. difficile colonization.