Oritavancin is a cell wall-targeting lipophilic glycopeptide molecule that belongs to the vancomycin class of antibiotics. It displays potent antimicrobial activities against vancomycin-resistant pathogens, however its molecular basis for such superior activity remains only partially understood. This paper reports a novel perspective on the mechanism of action by oritavancin by addressing fundamental questions of whether and how it is able to bind cell wall peptides including those strongly resistant to binding by vancomycin. We performed kinetic binding studies of vancomycin and oritavancin by surface plasmon resonance (SPR) spectroscopy in two cell wall model peptides, and provide evidence for much tighter adsorption by oritavancin to both model peptides than vancomycin. An additional set of data was collected from a competitive binding experiment and fluorescence spectroscopy, both of which are strongly indicative of its dual modes of interaction. In conclusion, this study reports a novel secondary binding motif adopted by oritavancin that enables to confer high affinity to even vancomycin-resistant cell wall peptides.

Biophysical basis for the high-affinity binding of a vancomycin-resistant cell wall peptide by oritavancin

255th National Meeting (2018)

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