Oritavancin Retains a High Affinity for a Vancomycin-Resistant Cell-Wall Precursor via Its Bivalent Motifs of Interaction

Despite its potent antibacterial activities against drug-resistant Gram-positive pathogens, oritavancin remains partially understood with respect to its primary mode of hydrogen bond interaction with a cell-wall peptide regarding the role of its lipophilic 4′-chlorobiphenyl moiety. Here we report a surface plasmon resonance (SPR) study performed in two cell-wall model surfaces, each prepared by immobilization with a vancomycin-susceptible Lys-d-Ala-d-Ala or vancomycin-resistant Lys-d-Ala-d-Lac peptide. Analysis of binding kinetics performed on the peptide surface showed that oritavancin bound ∼100–1000-fold more tightly than vancomycin on each model surface. Ligand competition experiments conducted by SPR and fluorescence spectroscopy provided evidence that such affinity enhancement can be attributed to its 4′-chlorobiphenyl moiety, possibly through a hydrophobic interaction that led to a gain of free energy with a contribution from enthalpy as suggested by a variable-temperature SPR experiment. On the ba...