Vancomycin-Teixobactin Conjugates.

Abstract

Vancomycin continues to be a widely used antibiotic of last resort in treating drug-resistant pathogens despite the emergence of vancomycin-resistant strains such as vancomycin-resistant Enterococci (VRE). This communication reports that conjugation of vancomycin to a second antibiotic that targets a different region of lipid II enhances and rescues its antibiotic activity. Conjugation of vancomycin to a minimal teixobactin pharmacophore in which residues 1-6 are replaced with an aromatic amide results in substantial enhancement in activity over the individual components or mixtures thereof. Three conjugates with minimum inhibitory concentrations (MICs) of 0.5 μg/mL against methicillin-resistant Staphylococcus aureus (MRSA) and 0.063-0.125 μg/mL against methicillin-susceptible Staphylococcus aureus (MSSA) were identified. Each of these conjugates is also active against VRE, even though the individual components are inactive, with the most active conjugate (Cbp-Lys₁₀-teixo_7-11-vanco) having an MIC of 2-4 μg/mL. These findings demonstrate that conjugation of vancomycin to a minimal teixobactin pharmacophore is an effective strategy for enhancing the activity of vancomycin against important Gram-positive pathogens.