With the extensive use of antibacterial agents, bacterial resistance has become a serious medical problem and infections caused by multidrug-resistant strains have posed new threat to the health of human beings.There is therefore an urgent need fornew antibacterial agents based on new molecular scaffolds with novel mode of action and activity against drug-resistant bacteria.

Pleuromutilin is a natural product with novel mode of action and possesses potent in vitro antibacterial activity against methicillin-resistant Staphylococcusaureus(MRSA),methicillin-resistant Staphylococcus epidermidis(MRSE)and penicillin-resistant Streptococcus pneumoniae (PRSP). Except for the topical drug Retapamulin which was launched in 2007 and NabrivaTherapeutics’BC-7013 and BC-3781 which have completed Phase I and Phase II clinical studies respectively, no systemic pleuromutilin antibiotics have made them into the market.

Using NabrivaTherapeutics’BC-7013 as a lead compound，prof. YANG Yushe，group designed and synthesized a series of novel pleuromutilin derivatives with hetero aromatic substitution. Extensive structure-activity relationship study, structure-metabolism relationship study and druggability optimization resuled in compound YLC-063. YLC-063 displayed good in vivo pharmacokinetic profiles in rats and showed in vivo efficacy comparable to linezolid in mice MSSA infection model after i.v. administration. More importantly, YLC-063 showed a much better in vivo efficacy than linezolid in mice MRSA infection model, which is worthy of further investigation.

This work has been published on Journal of Medicinal Chemistry（Chenyu Ling,† Liqiang Fu,† Suo Gao,† Hui Wang,‡ Yanqin Huang,§ Xiaoyan Chen† and Yushe Yang*,†Design, Synthesis, and Structure-Activity Relationship Studies of Novel Thioether Pleuromutilin Derivatives as Potent Antibacterial Agents J. Med.Chem.2014,56，4772-4795）.