The oxazolidinones: past, present, and future

Abstract

The success of linezolid stimulated significant efforts to discover new agents in the oxazolidinone class. Over a dozen oxazolidinones have reached the clinic, but many were discontinued due to lack of differentiated potency, inadequate pharmacokinetics, and safety risks that included myelosuppression. Four oxazolidinones are currently undergoing clinical evaluation. The Trius Therapeutics compound tedizolid phosphate (formerly known as torezolid phosphate, TR-701, DA-7218), the most advanced, is in phase 3 clinical trials for acute bacterial skin and skin structure infections. Rib-X completed two phase 2 studies for radezolid (Rx-01_667, RX-1741) in uncomplicated skin and skin structure infections and community-acquired pneumonia. Pfizer and AstraZeneca have each identified antitubercular compounds that have completed phase 1 studies: sutezolid (PNU-100480, PF-02341272) and AZD5847 (AZD2563), respectively. The oxazolidinones share a relatively low frequency of resistance largely due to the requirement of mutations in 23S ribosomal RNA genes. However, maintaining potency against strains carrying the mobile cfr gene poses a challenge for the oxazolidinone class, as well as other 50S ribosome inhibitors that target the peptidyl transferase center.

Targeting Antibiotic Resistance

“…So far, three classes of oxazolidinone resistance mechanisms have been characterized 31. The first involves mutations in the 23S rRNA central loop of domain V, the peptidyl transferase center.…”

“…Unfortunately most of these have failed owing to issues related to pharmacokinetic (PK) properties, safety profile, solubility, or lack of improvement of antimicrobial activity over linezolid. Therefore the two main challenges for successful second‐generation oxazolidinones are minimizing the myelosuppression safety signal and achieving adequate activity against linezolid‐resistant strains of bacteria 31. Two second‐generation oxazolidinones that attempt to solve these problems in a rational way will be presented herein.…”

Application and Progress of Organic Synthesis in the Discovery of Innovative Drugs

“…[48] . 从结构的演化和改进来看 [49] 分重要的两个酶, 是抗 HCV 治疗的理想靶点 [51] . 近年 来, 关于 HCV NS3/4A 蛋白酶和 NS5A/5B RNA 聚合酶 抑制剂的研究是抗 HCV 研究最为热门的方向 [52] .…”

Clinical results of linezolid in arthroplasty and trauma related infections

“…Adverse reactions to linezolid treatment are documented. Treatment has been associated with myelosuppression, with reports of anaemia, leucopenia and thrombocytopenia [15,34,35] . The side effects of treatment can be detected by close monitoring of blood with myelosuppression being reversible on stopping treatment [34] .…”