linezolid and radezolid

A series of novel oxazolidinone derivatives with nitrogen-containing fused heterocyclic moiety were designed and synthesized in this article. Their antibacterial activities were measured against S. aureus, MRSA and MSSA by MIC assay. Most of them exhibited potent activity against Gram-positive pathogens comparable to Linezolid and Radezolid. Compound 3b, which exhibited significant antibacterial activity with MIC values ranging 0.5-1.0 μg/mL, might be a promising drug candidate for further investigation.

Topics: Anti-Bacterial Agents; Drug Design; Drug Resistance, Bacterial; Microbial Sensitivity Tests; Nitrogen; Oxazolidinones; Staphylococcus aureus; Structure-Activity Relationship

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.

Topics: Acetamides; Animals; Anti-Bacterial Agents; Cells, Cultured; Dose-Response Relationship, Drug; Drug Resistance, Bacterial; Humans; Legionella pneumophila; Linezolid; Listeria monocytogenes; Microbial Sensitivity Tests; Oxazolidinones; Phagocytes; Rats; Staphylococcus aureus; Staphylococcus epidermidis

Radezolid (RX-1741) is the first biaryloxazolidinone in clinical development. It shows improved activity, including against linezolid-resistant strains. Radezolid differs from linezolid by the presence of a biaryl spacer and of a heteroaryl side chain, which increases the ionization and hydrophilicity of the molecule at physiological pH and confers to it a dibasic character. The aim of this study was to determine the accumulation and subcellular distribution of radezolid in phagocytic cells and to decipher the underlying mechanisms. In THP-1 human macrophages, J774 mouse macrophages, and human polymorphonuclear neutrophils, radezolid accumulated rapidly and reversibly (half-lives of approximately 6 min and 9 min for uptake and efflux, respectively) to reach, at equilibrium, a cellular concentration 11-fold higher than the extracellular one. This process was concentration and energy independent but pH dependent (accumulation was reduced to 20 to 30% of control values for cells in medium at a pH of <6 or in the presence of monensin, which collapses pH gradients between the extracellular and intracellular compartments). The accumulation at equilibrium was not affected by efflux pump inhibitors (verapamil and gemfibrozil) and was markedly reduced at 4 degrees C but was further increased in medium with low serum content. Subcellular fractionation studies demonstrated a dual subcellular distribution for radezolid, with approximately 60% of the drug colocalizing to the cytosol and approximately 40% to the lysosomes, with no specific association with mitochondria. These observations are compatible with a mechanism of transmembrane diffusion of the free fraction and partial segregation of radezolid in lysosomes by proton trapping, as previously described for macrolides.

Topics: Adenosine Triphosphate; Animals; Anti-Bacterial Agents; Biological Transport, Active; Cell Line; Culture Media; Half-Life; Humans; Hydrogen-Ion Concentration; In Vitro Techniques; Ionophores; Macrophages; Mice; Monensin; Neutrophils; Oxazolidinones; Phagocytes; Protein Binding; Temperature