1: J Antimicrob Chemother. 2008 Jun;61(6):1288-94. Epub 2008 Mar 27.

Cellular pharmacokinetics of telavancin, a novel lipoglycopeptide antibiotic, and
analysis of lysosomal changes in cultured eukaryotic cells (J774 mouse
macrophages and rat embryonic fibroblasts).

Barcia-Macay M, Mouaden F, Mingeot-Leclercq MP, Tulkens PM, Van Bambeke F.

Université catholique de Louvain, Faculté de Médecine, Unité de Pharmacologie
cellulaire et moléculaire, B-1200 Brussels, Belgium.

BACKGROUND: Telavancin is a lipoglycopeptide with multiple mechanisms of action
that include membrane-destabilizing effects towards bacterial cells. It shows
bactericidal activity against forms of Staphylococcus aureus (phagolysosomal
infection) with different resistance phenotypes [methicillin-resistant S. aureus,
vancomycin-intermediate S. aureus or vancomycin-resistant S. aureus]. We examine 
here the uptake, efflux and intracellular distribution of telavancin in
eukaryotic cells as well as its potential to induce lysosomal changes (in
comparison with vancomycin and oritavancin). METHODS: J774 macrophages and rat
embryo fibroblasts were exposed for up to 24 and 72 h to telavancin (5-90 mg/L). 
The following studies were performed: measurement of (14)C-labelled telavancin
cellular uptake and subcellular distribution (cell fractionation), determination 
of pericellular membrane integrity (lactate dehydrogenase release), electron
microscopy with morphometric analysis of changes in lysosome size and
determination of total phospholipid and cholesterol content. RESULTS: The uptake 
of telavancin proceeded linearly as a function of time and concentration in both 
cell types (clearance rate of approximately 10 mL/g of protein/h). Efflux
(macrophages) was approximately 5.7-fold slower. Telavancin subcellular
distribution was superimposable on that of a lysosomal marker
(N-acetyl-beta-hexosaminidase). It did not cause an increase in the release of
lactate dehydrogenase and did not induce significant increases in total
phospholipid or cholesterol content. It caused only mild morphological lysosomal 
alterations (similar to vancomycin and much less than oritavancin by morphometric
analysis). CONCLUSIONS: Telavancin is taken up by eukaryotic cells and localizes 
in lysosomes, causing mild morphological alterations without evidence of lipid
metabolism alterations. These data support our observations that telavancin is
active against intracellular S. aureus.

PMID: 18375379 [PubMed - in process]

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