The Bacteriocin Sublancin Restores Vancomycin efficacy against vancomycin-resistant enterococci <i>in vitro</i> and <i>in vivo</i>

Abstract Vancomycin-resistant enterococci (VRE) is one of the serious threat to global public health, with the diminishing effectiveness of antibiotics. There is an urgent need for novel strategies to control this multidrug-resistant bacterial infections. Here, our findings demonstrate that sublancin, a bacteriocin produced by Bacillus subtilis, exhibits intrinsic antibacterial activity and, more importantly, potentiates vancomycin, therapy restoring its efficacy against VRE. Using a series of in vitro assays, including fractional inhibitory concentration index, time-killing analysis, and resistance development assays, we show that sublancin significantly enhances the bactericidal effectiveness of vancomycin. In vivo , the sublancin-vancomycin combination therapy markedly reduced bacterial loads, improved svrvival rates in a Galleria mellonella model and enhanced bacterial clearance rates in a mouse model. Mechanistic studies using RT-PCR revealed that sublancin down-regulates the expression of the vanA resistance gene cluster. All in all, these findings make vancomycin and this antibiotic peptide combination as a promising candidatese to enhance vancomycin efficacy and overcome VRE infections, potentially through inteference with resistance gene expression.