Repurposing antibacterial drugs identifies ridinilazole and CRS3123 as promising candidates against vancomycin-resistant enterococci

Vancomycin-resistant enterococci (VRE) represent a growing threat to public health due to their increasing prevalence and limited treatment options. The urgent need for alternative therapeutics highlights the value of novel approaches such as drug repurposing to identify effective antimicrobial agents. In this study, we screened a library of 1,135 antibacterial compounds to identify candidates active against VRE. Fifty-eight compounds demonstrated measurable activity, with ridinilazole and CRS3123 emerging as the most promising. Both exhibited potent antibacterial activity in the nanomolar range against multiple Enterococcus species, including vancomycin-resistant and vancomycin-sensitive E. faecium, E. faecalis, E. hirae, and E. durans. CRS3123 displayed exceptional potency, with MIC values of < 0.007 µg/mL for most strains. Ridinilazole exhibited a broader MIC spectrum with E. faecium highly sensitive (< 0.007-0.25 µg/mL) and E. faecalis less susceptible (0.5->64 µg/mL). Both compounds also displayed low cytotoxicity in Vero cells and no hemolytic activity, suggesting a favorable safety profile. In vivo studies using the C. elegans model confirmed potent efficacy, with CRS3123 reducing both E. faecium and E. faecalis burden similar to linezolid while ridinilazole were effective against E. faecium only. These findings support ridinilazole and CRS3123 as promising candidates for further VRE therapeutic development.