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 MP. 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] Related Links Interaction of the antimicrobial peptide pheromone Plantaricin A with model membranes: implications for a novel mechanism of action. [Biochim Biophys Acta. 2006] PMID:16806056 Interaction of the macrolide antibiotic azithromycin with lipid bilayers: effect on membrane organization, fluidity, and permeability. [Pharm Res. 2005] PMID:15835753 Exploring membrane selectivity of the antimicrobial peptide KIGAKI using solid-state NMR spectroscopy. [Biochim Biophys Acta. 2006] PMID:16537078 Effects of lipid composition on membrane permeabilization by sticholysin I and II, two cytolysins of the sea anemone Stichodactyla helianthus. [Biophys J. 2001] PMID:11371451 Phosphatidylethanolamine-phosphatidylglycerol bilayer as a model of the inner bacterial membrane. [Biophys J. 2005] PMID:15556990