Multidrug-resistant bacteria represent one of the greatest challenges for modern medicine. The increasing resistance against glycopeptide antibiotics compromises the efficacy of vancomycin, for a long time considered as the last resort for the treatment of resistant Gram-positive bacteria.^1,2 To reestablish its activity, polycationic peptides were conjugated to vancomycin. Several derivatives that bear the poly arginine peptide moiety at four different sites of vancomycin were synthesized through site-specific conjugation.^3-5

The lead conjugate V_N-R6C showed high antimicrobial activity (up to 1000-fold increased) on 15 clinical isolates of linezolid- and vancomycin-resistant enterococci (LVRE, E. faecium) as well as on 25 clinical isolates of vancomycin resistant E. faecium and E. faecalis. The higher antimicrobial activity was also demonstrated by improved killing kinetics against selected strains of enterococci and staphylococci. Furthermore, the antimicrobial potential of the lead candidate V_N-R6C could be demonstrated in a murine in vivo systemic infection model. Blocking experiments using d‑Ala‑d‑Ala revealed a mode of action beyond the inhibition of cell-wall formation. Further, the peptide modification enables modulation of the pharmacokinetics allowing specific organ targeting.

Encapsulation of V_N-R6C in PEGylated liposomal nanocarrier systems prolonged the half-life of the drug after intravenous administration: studies in Wistar rats revealed a significantly prolonged circulation of the liposomal antibiotic. Microdilution testing proved that the liposomal encapsulation of V_N-R6C does not diminish the antimicrobial activity against staphylococci and enterococci. Highlighting its great potency, liposomal V_N-R6C exhibited a superior therapeutic efficacy when compared to the free drug in a Galleria mellonella larvae infection model.

Beyond vancomycin, the strategy could be proven effective for other glycopeptide and cell wall targeting antibiotics, indicating its potential applicability as a platform technology (referred to as ROVANCE technology).