title: Cellular pharmacokinetics of telavancin, a novel lipoglycopeptide antibiotic, and analysis of lysosomal changes in cultured eukaryotic cells (J774 mouse macrophages and rat embryonic fibroblasts).
abstract: 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.
authors: Université catholique de Louvain, Faculté de Médecine, Unité de Pharmacologie cellulaire et moléculaire, B-1200 Brussels, Belgium.
authors: Maritza
authors: M
authors: Barcia-Macay
authors: Fatima
authors: F
authors: Mouaden
authors: Marie-Paule
authors: MP
authors: Mingeot-Leclercq
authors: Paul M
authors: PM
authors: Tulkens
authors: Françoise
authors: F
authors: Van Bambeke
mesh_terms: D000617:Aminoglycosides / Q000378:metabolism* / Q000633:toxicity*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000378:metabolism* / Q000633:toxicity*; D002250:Carbon Radioisotopes / Q000378:metabolism; D002458:Cell Fractionation; D002460:Cell Line; D002478:Cells, Cultured; D002784:Cholesterol / Q000032:analysis; D005347:Fibroblasts / Q000737:chemistry / Q000187:drug effects*; D000077427:Lipoglycopeptides; D008247:Lysosomes / Q000737:chemistry / Q000187:drug effects* / Q000648:ultrastructure; D008264:Macrophages / Q000187:drug effects*; D051379:Mice; D046529:Microscopy, Electron, Transmission; D010743:Phospholipids / Q000032:analysis; D051381:Rats; D013997:Time Factors
chemical_list: D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D002250:Carbon Radioisotopes; D000077427:Lipoglycopeptides; D010743:Phospholipids; D002784:Cholesterol; C487637:telavancin