1. Biochim Biophys Acta. 2010 Oct;1798(10):1876-85. Epub 2010 Jun 23.

Interactions of oritavancin, a new semi-synthetic lipoglycopeptide, with lipids
extracted from Staphylococcus aureus.

Domenech O, Dufrêne YF, Van Bambeke F, Tulkens PM, Mingeot-Leclercq MP.

Université catholique de Louvain, Louvain Drug Research Institute, Unité de
pharmacologie cellulaire et moléculaire, UCL 73.70, avenue E. Mounier 73, B-1200 
Bruxelles, Belgium.

Oritavancin, a lipoglycopeptide with marked bactericidal activity against
vancomycin-resistant Staphylococcus aureus and enterococci, induces calcein
release from CL:POPE and POPG:POPE liposomes, an effect enhanced by an increase
in POPG:POPE ratio, and decreased when replacing POPG by DPPG (Domenech et al.,
Biochim Biophys Acta 2009; 1788:1832-40). Using vesicles prepared from lipids
extracted from S. aureus, we showed that oritavancin induces holes, erosion of
the edges, and decrease of the thickness of the supported lipid bilayers (atomic 
force microscopy; AFM). Oritavancin also induced an increase of membrane
permeability (calcein release) on a time- and dose-dependent manner. These
effects were probably related to the ability of the drug to bind to lipid
bilayers as shown by 8-anilino-1- naphthalene sulfonic acid (ANS) assay.
Interaction of oritavancin with phospholipids at the level of their glycerol
backbone and hydrophobic domain was studied by monitoring changes of Laurdan
excitation generalized polarization (GP(ex)) and 1,6-diphenyl-1,3,5-hexatriene
(DPH) fluorescence anisotropy upon temperature increase. Oritavancin increased
GP(ex) values and the transition temperature, indicating a more ordered structure
at the level of the glycerol backbone. Oritavancin slightly decreased DPH
fluorescence depolarization intensities, suggesting an increase in fluidity at
the level of acyl chains. Together, our data confirm the interaction of
oritavancin with lipids and the potential role of a rigidifying effect at the
level of glycerol backbone for membrane permeabilization. This work shows how AFM
and biophysical methods may help in characterizing drug-membrane interactions,
and sheds further light on the mode of action of oritavancin.

PMID: 20599683 [PubMed - indexed for MEDLINE]