1: Antimicrob Agents Chemother. 2005 May;49(5):1695-700. 

Mixed-Lipid Storage Disorder Induced in Macrophages and Fibroblasts by
Oritavancin (LY333328), a New Glycopeptide Antibiotic with Exceptional Cellular

Van Bambeke F, Saffran J, Mingeot-Leclercq MP, Tulkens PM.

UCL 7370 avenue Mounier 73, 1200 Brussels, Belgium. vanbambeke@facm.ucl.ac.be.

Oritavancin, a semisynthetic derivative of vancomycin endowed with a cationic
amphiphilic character, accumulates to large extent in the lysosomes of
eukaryotic cells (F. Van Bambeke, S. Carryn, C. Seral, H. Chanteux, D. Tyteca,
M. P. Mingeot-Leclercq, and P. M. Tulkens, Antimicrob. Agents Chemother.
48:2853-2860, 2004). In the present study, we examined whether this accumulation
could cause cell alterations in phagocytic (J774 mouse macrophages) and
nonphagocytic (rat embryo fibroblasts) cells exposed to clinically meaningful
(0- to 40-mg/liter) concentrations of oritavancin. Optical and electronic
microscopy evidenced conspicuous alterations of the vacuolar apparatus in both
cell types, characterized by the deposition of concentric lamellar structures,
finely granular material, or other less-defined osmiophilic material, often
deposed in giant vesicles. Biochemical studies showed an accumulation of
phospholipids (1.5x control values) and free and esterified cholesterol (3 to 4x
control values for total cholesterol). Accumulation of these lipids was in close
relation to that of oritavancin (excess phospholipid/oritavancin and excess
cholesterol/oritavancin molar ratios of 2 to 3 and 3 to 5, respectively).
Cholesterol accumulation was rapid and reversible, and that of phospholipids was
slower and poorly reversible. Vancomycin and teicoplanin, used as controls (50
and 100 mg/liter, respectively), did not cause any significant change in the
lipid content of fibroblasts. The data therefore suggest that oritavancin has
the potential to cause a mixed-lipid storage disorder in eukaryotic cells.

PMID: 15855483 [PubMed - in process]