Oritavancin disrupts membrane integrity of Staphylococcus aureus and vancomycin-resistant enterococci to effect rapid bacterial killing

Abstract

Oritavancin is an investigational lipoglycopeptide in clinical development for the treatment of acute bacterial skin and skin structure infections. In this study, we demonstrate that oritavancin causes bacterial membrane depolarization and permeabilization leading to cell death of Gram-positive pathogens and that these effects are attributable to the 4'-chlorobiphenylmethyl group of the molecule.

FIG. 1.

Oritavancin but not its precursor chloroeremomycin or vancomycin disrupts bacterial membrane integrity, leading to concomitant killing of hVISA ATCC 700698. (A to D) Effects of oritavancin and comparator agents on membrane depolarization (A), membrane permeability (B), cell viability (C), and the correlation between membrane depolarization and cell killing (D). Drug concentrations: control (✳); oritavancin at 4 μg/ml (▪), 8 μg/ml (○) and 16 μg/ml (•); 16 μg/ml chloroeremomycin (⋄); 16 μg/ml vancomycin (⧫). Note that the chloroeremomycin and vancomycin curves overlap in panel A and with the control curve in panel C. The limit of detection (200 CFU) is indicated as a dashed line in panel C.

FIG. 2.

Oritavancin-induced membrane depolarization and cell killing of VISA, VRSA, and VREF isolates are tightly correlated. (A to C) Correlations were determined for VISA ATCC 700699 (A), VRSA VRS5 (B), and VanB VREF ATCC 51299 (C). Oritavancin was used at 0.5 μg/ml (▵), 1 μg/ml (▴), 2 μg/ml (□), 4 μg/ml (▪), 8 μg/ml (○), and 16 μg/ml (•).