1: Biochim Biophys Acta. 2009 Sep;1788(9):1832-40. Epub 2009 May 18.

Interactions of oritavancin, a new lipoglycopeptide derived from vancomycin, with
phospholipid bilayers: Effect on membrane permeability and nanoscale lipid
membrane organization.

Domenech O, Francius G, Tulkens PM, Van Bambeke F, Dufrêne Y, Mingeot-Leclercq

Université catholique de Louvain, Faculté de Médecine, Louvain Drug Research
Institute, Unité de pharmacologie cellulaire et moléculaire, UCL 73.70, B-1200
Bruxelles, Belgium.

Antibiotics acting on bacterial membranes are receiving increasing attention
because of widespread resistance to agents acting on other targets and of
potentially improved bactericidal effects. Oritavancin is a amphiphilic
derivative of vancomycin showing fast and extensive killing activities against
multi-resistant (including vancomycin insusceptible) Gram-positive organisms with
no marked toxicity towards eukaryotic cells. We have undertaken to characterize
the interactions of oritavancin with phospholipid bilayers, using liposomes (LUV)
and supported bilayers made of cardiolipin (CL) or phosphatidylglycerol (POPG)
and phosphatidylethanolamine (POPE), all abundant in Gram-positive organisms.
Changes in membrane permeability were followed by the release of calcein
entrapped in liposomes at self-quenching concentrations, and changes in nanoscale
lipid organization examined by Atomic Force Microscopy (AFM). Oritavancin caused 
a fast (<5 min) and complete (>95%) release of calcein from CL:POPE liposomes,
and a slower but still substantial (50% in 60 min) release from POPG:POPE
liposomes, which was (i) concentration-dependent (0-600 nM; [microbiologically
meaningful concentrations]); (ii) enhanced by an increase in POPG:POPE ratio, and
decreased when replacing POPG by DPPG. AFM of CL:POPE supported bilayers showed
that oritavancin (84 nM) caused a remodeling of the lipid domains combined with a
redisposition of the drug and degradation of the borders. In all the above
studies, vancomycin was without a significant effect at 5.5 muM. Electrostatic
interactions, together with lipid curvature, lipid polymorphism as well of
fluidity play a critical role for the permeabilization of lipid bilayer and
changes in lipid organization induced by oritavancin.

PMID: 19450541 [PubMed - in process]

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