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, Maritza;Mouaden, Fatima;Mingeot-Leclercq, Marie-Paule;Tulkens, Paul M.;Van Bambeke, Françoise
(2008) Journal of Antimicrobial Chemotherapy — Vol. 61, n° 6, p. 1288-1294 (2008)

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Authors
  • Barcia Macay, MaritzaUCLouvain
    Author
  • Mouaden, FatimaUCLouvain
    Author
  • Mingeot-Leclercq, Marie-PauleUCLouvain
    Author
  • Tulkens, Paul M.UCLouvain
    Author
  • Van Bambeke, Françoiseorcid-logoUCLouvain
    Author
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.
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Barcia Macay, M., Mouaden, F., Mingeot-Leclercq, M.-P., Tulkens, P. M., & Van Bambeke, F. (2008). Cellular pharmacokinetics of telavancin, a novel lipoglycopeptide antibiotic, and analysis of lysosomal changes in cultured eukaryotic cells (J774 mouse macrophages and rat embryonic fibroblasts). Journal of Antimicrobial Chemotherapy, 61(6), 1288-1294. https://doi.org/10.1093/jac/dkn120 (Original work published 2008)