Discovery of Potent Benzocycloalkane Derived Diapophytoene Desaturase Inhibitors with an Enhanced Safety Profile for the Treatment of MRSA, VISA, and LRSA Infections

doi:10.1021/acsinfecdis.7b00259

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	Discovery of Potent Benzocycloalkane Derived Diapophytoene Desaturase Inhibitors with an Enhanced Safety Profile for the Treatment of MRSA, VISA, and LRSA Infections
	Li, Baoli 2; Ni, Shuaishuai 2; Chen, Feifei 1; Mao, Fei 2; Wei, Hanwen 2; Liu, Yifu 2; Zhu, Jin 2; Lan, Lefu1 ; Li, Jian 2
刊名	ACS INFECTIOUS DISEASES
	2018-03
卷号	4 期号:3 页码:208-217
关键词	Staphylococcus aureus diapophytoene desaturase methicillin-resistant Staphylococcus aureus hERG safety
ISSN号	2373-8227
DOI	10.1021/acsinfecdis.7b00259
文献子类	Article
英文摘要	Blocking the biosynthesis process of staphyloxanthin has emerged as a promising antivirulence strategy. Our previous research revealed that diapophytoene desaturase was an attractive and druggable target against infections caused by pigmented Staphylococcus aureus. Benzocycloalkane-derived compounds were effective inhibitors of diapophytoene desaturase but limited by high hERG (human Ether-a-go-go Related Gene) inhibition activity. Here, we identified a new type of benzo-hepta-containing cycloalkane derivative as diapophytoene desaturase inhibitors. Among the fifty-eight analogues, 48 (hERG inhibition activity, half maximal inhibitory concentration, IC50, of 16.1 mu M) and 51 (hERG inhibition activity, IC50 > 40 mu M) were distinguished for effectively inhibiting the pigment production of Staphylococcus aureus Newman and three methicillin-resistant Staphylococcus aureus strains, and the four strains were highly sensitize to hydrogen peroxide killing without a bactericidal growth effect. In an in vivo assay, 48 and 51 displayed a comparable effect with linezolid and vancomycin in livers and hearts in mice against Staphylococcus aureus Newman and a more considerable effect against Mu50 and NRS271 with normal administration.
资助项目	National Key R&D Program of China[2017YFB0202600] ; National Natural Science Foundation of China[21672064] ; "Shu Guang" project - Shanghai Municipal Education Commission[00000000] ; "Shu Guang" project - Shanghai Education Development Foundation[14SG28] ; Fundamental Research Funds for the Central Universities[00000000]
WOS关键词	RESISTANT STAPHYLOCOCCUS-AUREUS ; VIRULENCE ; BIOSYNTHESIS ; STAPHYLOXANTHIN ; NEUTROPHILS ; EPIDEMIC ; CRTN
WOS研究方向	Pharmacology & Pharmacy ; Infectious Diseases
语种	英语
出版者	AMER CHEMICAL SOC
WOS记录号	WOS:000427443200001
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/279865]
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.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, 646 Songtao Rd, Shanghai 201203, Peoples R China 2.East China Univ Sci & Technol, Sch Pharm, Shanghai Key Lab New Drug Design, 130 Meilong Rd, Shanghai 200237, Peoples R China;
推荐引用方式 GB/T 7714	Li, Baoli,Ni, Shuaishuai,Chen, Feifei,et al. Discovery of Potent Benzocycloalkane Derived Diapophytoene Desaturase Inhibitors with an Enhanced Safety Profile for the Treatment of MRSA, VISA, and LRSA Infections[J]. ACS INFECTIOUS DISEASES,2018,4(3):208-217.
APA	Li, Baoli.,Ni, Shuaishuai.,Chen, Feifei.,Mao, Fei.,Wei, Hanwen.,...&Li, Jian.(2018).Discovery of Potent Benzocycloalkane Derived Diapophytoene Desaturase Inhibitors with an Enhanced Safety Profile for the Treatment of MRSA, VISA, and LRSA Infections.ACS INFECTIOUS DISEASES,4(3),208-217.
MLA	Li, Baoli,et al."Discovery of Potent Benzocycloalkane Derived Diapophytoene Desaturase Inhibitors with an Enhanced Safety Profile for the Treatment of MRSA, VISA, and LRSA Infections".ACS INFECTIOUS DISEASES 4.3(2018):208-217.