Cellular pharmacodynamics of the novel biaryloxazolidinone radezolid : studies with infected phagocytic and non-phagocytic cells, using Staphylococcus aureus, Staphylococcus epidermidis, Listeria monocytogenes, and Legionella pneumophila

Lemaire, Sandrine;Kosowska-Shick, Klaudia;Appelbaum, Peter C;Verween, Gunther;Van Bambeke, Françoise;et.al.
(2010) Antimicrobial Agents and Chemotherapy — Vol. 54, n° 6, p. 2549-2559 (2010)

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Authors
  • Lemaire, SandrineUCLouvain
    Author
  • Kosowska-Shick, Klaudia
    Author
  • Appelbaum, Peter C
    Author
  • Verween, Gunther
    Author
  • Tulkens, Paul M.UCLouvain
    Author
  • Van Bambeke, Françoiseorcid-logoUCLouvain
    Author
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Abstract
Radezolid is a novel biaryloxazolidinone in clinical development, which shows improved activity including against linezolid-resistant strains. In a companion paper (Lemaire et al. accepted [AAC-1723-09]), we showed that radezolid accumulates about 11-fold in phagocytic cells with approximately 60 % of the drug localized in their cytosol and approximately 40 % in their lysosomes. The present study examines its activity against (a) bacteria infecting human THP-1 macrophages and located in different subcellular compartments (Listeria monocytogenes, cytosol; Legionella pneumophila; vacuoles; Staphylococcus aureus and epidermidis, mainly phagolysosomal), (b) strains of S. aureus with clinically-relevant mechanisms of resistance, and (c) isogenic linezolid-susceptible and -resistant S. aureus infecting a series of phagocytic and non-phagocytic cells. Radezolid accumulated to similar levels ( approximately 10-fold) in all cell types (human keratinocytes, endothelial cells, bronchial epithelial cells, osteoblasts, macrophages, and rat embryo fibroblasts). At equivalent weight concentrations, radezolid proved consistently 10-fold more potent than linezolid in all these models, irrespective of the bacterial species and resistance phenotype, or of the cell type infected. This results from its higher intrinsic activity and higher cellular accumulation. Time kill-curves showed that radezolid activity was more rapid than that of linezolid both in broth and in infected macrophages. These data suggest the potential interest of radezolid for recurrent or persistent infections where intracellular foci play a determinant role.
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Lemaire, S., Kosowska-Shick, K., Appelbaum, P. C., Verween, G., Tulkens, P. M., & Van Bambeke, F. (2010). Cellular pharmacodynamics of the novel biaryloxazolidinone radezolid : studies with infected phagocytic and non-phagocytic cells, using Staphylococcus aureus, Staphylococcus epidermidis, Listeria monocytogenes, and Legionella pneumophila. Antimicrobial Agents and Chemotherapy, 54(6), 2549-2559. https://doi.org/10.1128/AAC.01724-09 (Original work published 2010)