Oxazolidinone structure-activity relationships leading to linezolid.
The development of bacterial resistance to currently available antibacterial agents is a growing global health problem. Of particular concern are infections caused by multidrug-resistant Gram-positive pathogens which are responsible for significant morbidity and mortality in both the hospital and community settings. A number of solutions to the problem of bacterial resistance are possible. The most common approach is to continue modifying existing classes of antibacterial agents to provide new analogues with improved attributes. Other successful strategies are to combine existing antibacterial agents with other drugs as well as the development of improved diagnostic procedures that may lead to rapid identification of the causative pathogen and permit the use of antibacterial agents with a narrow spectrum of activity. Finally, and most importantly, the discovery of novel classes of antibacterial agents employing new mechanisms of action has considerable promise. Such agents would exhibit a lack of cross-resistance with existing antimicrobial drugs. This review describes the work leading to the discovery of linezolid, the first clinically useful oxazolidinone antibacterial agent.
Barbachyn
Michael R
MR
Medicinal Chemistry Research, Pharmacia Corporation, 7000 Portage Road, Kalamazoo, MI 49001, USA. michael.r.barbachyn@pharmacia.com
Ford
Charles W
CW
D000081:Acetamides / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D006094:Gram-Positive Bacteria / Q000187:drug effects*; D016908:Gram-Positive Bacterial Infections / Q000188:drug therapy; D000069349:Linezolid; D015394:Molecular Structure; D023303:Oxazolidinones / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D013329:Structure-Activity Relationship
D000081:Acetamides; D000900:Anti-Bacterial Agents; D023303:Oxazolidinones; D000069349:Linezolid