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

doi:10.1021/acs.jmedchem.6b00122

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	Discovery of Benzocycloalkane Derivatives Efficiently Blocking Bacterial Virulence for the Treatment of Methicillin-Resistant S. aureus (MRSA) Infections by Targeting Diapophytoene Desaturase (CrtN)
	Wang, Youxin 2; Di, Hongxia 3; Chen, Feifei 3; Xu, Yong 1; Xiao, Qiang 1; Wang, Xuehai 4; Wei, Hanwen 2; Lu, Yanli 2; Zhang, Lingling 2; Zhu, Jin 2
刊名	JOURNAL OF MEDICINAL CHEMISTRY
	2016-05-26
卷号	59 期号:10 页码:4831-4848
ISSN号	0022-2623
DOI	10.1021/acs.jmedchem.6b00122
文献子类	Article
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.
资助项目	National Natural Science Foundation of China[21222211] ; National Natural Science Foundation of China[21372001] ; National Natural Science Foundation of China[21472207] ; "Shu Guang" project - Shanghai Municipal Education Commission[00000000] ; Shanghai Education Development Foundation[14SG28] ; Program for New Century Excellent Talents in University[NCET-12-0853] ; Fundamental Research Funds for the Central Universities[00000000]
WOS关键词	STAPHYLOCOCCUS-AUREUS ; STAPHYLOXANTHIN ; ANTIVIRULENCE ; BIOSYNTHESIS ; NAFTIFINE ; EPIDEMIC ; PARADIGM
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	AMER CHEMICAL SOC
WOS记录号	WOS:000376840600032
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/276034]
专题	药理学第三研究室中科院受体结构与功能重点实验室新药研究国家重点实验室
通讯作者	Lan, Lefu; Li, Jian
作者单位	1.Hubei Biopharmaceut Ind Technol Inst Inc, Wuhan 430075, Peoples R China; 2.E China Univ Sci & Technol, Sch Pharm, Shanghai Key Lab New Drug Design, Shanghai 200237, Peoples R China; 3.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China; 4.Humanwell Healthcare Grp Co Ltd, Wuhan 430075, Peoples R China
推荐引用方式 GB/T 7714	Wang, Youxin,Di, Hongxia,Chen, Feifei,et al. Discovery of Benzocycloalkane Derivatives Efficiently Blocking Bacterial Virulence for the Treatment of Methicillin-Resistant S. aureus (MRSA) Infections by Targeting Diapophytoene Desaturase (CrtN)[J]. JOURNAL OF MEDICINAL CHEMISTRY,2016,59(10):4831-4848.
APA	Wang, Youxin.,Di, Hongxia.,Chen, Feifei.,Xu, Yong.,Xiao, Qiang.,...&Li, Jian.(2016).Discovery of Benzocycloalkane Derivatives Efficiently Blocking Bacterial Virulence for the Treatment of Methicillin-Resistant S. aureus (MRSA) Infections by Targeting Diapophytoene Desaturase (CrtN).JOURNAL OF MEDICINAL CHEMISTRY,59(10),4831-4848.
MLA	Wang, Youxin,et al."Discovery of Benzocycloalkane Derivatives Efficiently Blocking Bacterial Virulence for the Treatment of Methicillin-Resistant S. aureus (MRSA) Infections by Targeting Diapophytoene Desaturase (CrtN)".JOURNAL OF MEDICINAL CHEMISTRY 59.10(2016):4831-4848.