Antibiotic resistance is an emerging threat to global health. Infections caused by resistant Gram-positive bacteria such as methicillin-resistant Staphylococcus aureus (MRSA), penicillin-resistant Streptococcus pneumoniae (PRSP), and vancomycin-resistant Enterococcus faecalis (VRE) are the most serious problems.

Linezolid, the first and only oxazolidinonedrug, was approved in 2000 by the Food and Drug Administration (FDA) for the treatment of multidrug resistant Gram-positive bacterial infections. However, after its commercial release, linezolid-resistant strains emerged in the clinic, underscoring the increasingly urgent need for improved antibiotics with potent antimicrobial activity, especially against linezolid-resistant strains.

Dr. YANG Yushe’s group of Shanghai Institute of Materia Medica, Chinese Academy of Sciences, has identified a novel class of antibacterial agent, the benzoxazinyl-oxazolidinones. Nonaromatic hetero-cycles or aromatic rings attached to the [6,6,5] tricyclic fused core structure significantly improved the potency. Most of the target compounds exhibited potent activity against Gram-positive pathogens, and particularly noteworthy was the excellent activity shown by compounds 45, 46 and 72 against linezolid-resistant strains. Compound 45 exhibited an excellent PK profile as well as activity that were 3 to 4 fold higher than linezolid in vivo. The favorable in vitro and in vivo activities of this compound, combined with its excellent PK profile, make it a very promising drug candidate. Evaluation of the safety of this drug candidate is currently under investigation.

This work was supported by the National New Drug Development Program of China and the National Natural Science Foundation of China. This work has been published on Journal of Medicinal Chemistry (2011, 54, 7493-7502).