Radezolid is a novel biaryloxazolidinone in clinical development which shows improved activity, including against
linezolid-resistant strains. In a companion paper (29), we showed that
radezolid accumulates about 11-fold in phagocytic cells, with approximately 60% of the
drug localized in the cytosol and approximately 40% in the lysosomes of the cells. The present study examines its activity against (i) bacteria infecting human THP-1 macrophages and located in different subcellular compartments (Listeria monocytogenes, cytosol; Legionella pneumophila, vacuoles; Staphylococcus aureus and Staphylococcus epidermidis, mainly phagolysosomal), (ii) strains of S. aureus with clinically relevant mechanisms of resistance, and (iii) isogenic
linezolid-susceptible and -resistant S. aureus strains infecting a series of phagocytic and nonphagocytic 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's 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.