Oxazolidinone Antibacterial Agents: A Critical Review

This review covers recent developments in several important aspects of research on oxazolidinone antibacterial agents. Structure-activity relationships are first discussed, emphasizing bioisosteric replacements for the both the oxazolidinone ring and the N-acetylaminomethyl group at C-5. The oxazolidinones have a mechanism of action that is distinct from other antibacterial agents, whereby protein synthesis is inhibited prior to initiation. Studies aimed at determining how the oxazolidinones bind to the bacterial ribosome and interfere with peptidyl transferase activity are described in detail, and are then related to the nature of the changes in the ribosomal RNA leading to resistance. Toxicity of the oxazolidinones remains a critical issue, in that early lead compounds exhibited lethal toxicity in animal studies. Preclinical and clinical safety studies of both eperezolid and linezolid are summarized, giving emphasis to histopathological effects observed in early animal studies. These studies are then related to thrombocytopenia and pancytopenia observed in patients treated with linezolid for extended time periods. Finally, studies to determine the nature and potential severity of drug-drug interactions in patients undergoing linezolid therapy are discussed.