文献类型：期刊文献

英文题名：Discovery of Benzocycloalkane Derivatives Efficiently Blocking Bacterial Virulence for the Treatment of Methicillin-Resistant S. aureus (MRSA) Infections by Targeting Diapophytoene Desaturase (CrtN)

作者：Wang, Youxin[1];Di, Hongxia[2];Chen, Feifei[2];Xu, Yong[3];Xiao, Qiang[3];Wang, Xuehai[4];Wei, Hanwen[1];Lu, Yanli[1];Zhang, Lingling[1];Zhu, Jin[1];Lan, Lefu[2];Li, Jian[1]

机构：[1]E China Univ Sci & Technol, Sch Pharm, Shanghai Key Lab New Drug Design, Shanghai 200237, Peoples R China;[2]Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China;[3]Hubei Biopharmaceut Ind Technol Inst Inc, Wuhan 430075, Peoples R China;[4]Humanwell Healthcare Grp Co Ltd, Wuhan 430075, Peoples R China

年份：2016

卷号：59

期号：10

起止页码：4831

外文期刊名：JOURNAL OF MEDICINAL CHEMISTRY

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000376840600032)】；

基金：Financial support of this research provided by the National Natural Science Foundation of China (Grants 21222211, 21372001, and 21472207), the "Shu Guang" project supported by Shanghai Municipal Education Commission and Shanghai Education Development Foundation (Grant 14SG28), the Program for New Century Excellent Talents in University (Grant NCET-12-0853), and the Fundamental Research Funds for the Central Universities is gratefully acknowledged.

语种：英文

摘要：Antivirulence strategies are now attracting interest for the inherent mechanism of action advantages. In our previous work, diapophytoene desaturase (CrtN) was identified to be an attractive and drugable target for fighting pigmented S. aureus infections. In this research, we developed a series of effective benzocycloalkane-derived CrtN inhibitors with submicromolar IC50. Analogue 8 blocked the pigment biosynthesis of three MRSA strains with a nanomolar IC50 value. Corresponding to its mode of action, 8 did not function as a bactericidal agent. 8 could sensitize S. aureus to immune clearance. In vivo, 8 was proven to be efficacious in an S. aureus Newman sepsis model and abscess formation model. For two typical MRSAs,. USA400 MW2 and Mu50, 8 significantly decreased the staphylococcal loads in the liver and kidneys. Moreover, 8 showed minimal antifungal activity compared to that of NTF. In summary, 8 has the potential to be developed as a therapeutic drug, especially against intractable MRSA issues.