Antagonizing Vancomycin Resistance in Enterococcus by Surface Localized Antimicrobial Display-Derived Peptides

Decreasing the therapeutic pipeline for vancomycin-resistant Enterococci (VRE) calls for novel strategies to enhance our antibacterial arsenal. Herein, we investigated the potential applications of surface localized antimicrobial display (SLAY)-derived cationic peptides in the fight against VanA operon mediated vancomycin-resistant Enterococcus. Through determining their antibacterial spectrum, we found that SLAY peptide 1/2 displayed moderate bactericidal activity against Enterococcus with minimal inhibitory concentration (MIC) values of 2–8 μg/mL. Furthermore, we observed a significant synergistic activity between SLAY-P1 and vancomycin against VRE. Mechanistic studies demonstrated that SLAY-P1 specifically inhibits transcription of the vanRS two-component system, thereby restoring vancomycin activity and resulting in the accumulation of the cell wall precursor. Meaningfully, the combination of SLAY-P1 and vancomycin prevents the emergence of vancomycin resistance. Consistent with in vitro synergistic results, the addition of SLAY-P1 significantly enhanced the survival rates of Galleria mellonella larvae compared with vancomycin monotherapy. Taken together, these results suggested that SLAY-derived cationic peptides not only display antibacterial activity against VRE but also reverse vancomycin resistance in Enterococcus, providing promising candidates for combating vancomycin-resistant pathogens.