Novel staphyloxanthin inhibitors with improved potency against multidrug resistant Staphylococcus aureus
Novel staphyloxanthin inhibitors with improved potency against multidrug resistant Staphylococcus aureus
复制标题
新型葡萄球菌黄素抑制剂，对多重耐药金黄色葡萄球菌具有更强的功效
DOI：
10.1021/acsmedchemlett.7b00501
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发表时间：
2018
影响因子：
4.2
通讯作者：
Jian Li
中科院分区：
文献类型：
--
作者：
Shuaishuai Ni;Baoli Li;Feifei Chen;Hanwen Wei;Fei Mao;Yifu Liu;Yixiang Xu;Xiaoxia Qiu;Xiaokang Li;Wenwen Liu;Linghao Hu;Dazheng Ling;Manjiong Wang;Xinyu Zheng;Jin Zhu;Lefu Lan;Jian Li
二脱八氢番茄红素去饱和酶（CrtN）是一个潜在的新目标，干预毒力因子葡萄黄素的生物合成。本研究针对先导化合物4a的缺陷，设计合成了38个1，4-苯并二氧六环类CrtN抑制剂。Derivative 47显示出上级的色素抑制活性、更好的hERG抑制特性和水溶性，并在体外显著致敏MRSA菌株以进行免疫清除。值得注意的是，47对色素沉着S显示出优异的功效。aureusNewman、Mu 50（万古霉素中间型MRSA，VISA）和NRS 271（利奈唑胺耐药MRSA，LRSA）的体内耐药率与利奈唑胺和万古霉素相当。
Diapophytoene desaturase (CrtN) is a potential novel target for intervening in the biosynthesis of the virulence factor staphyloxanthin. In this study, 38 1,4-benzodioxan-derived CrtN inhibitors were designed and synthesized to overwhelm the defects of leading compound4a. Derivative47displayed superior pigment inhibitory activity, better hERG inhibitory properties and water solubility, and significantly sensitized MRSA strains to immune clearance in vitro. Notably,47displayed excellent efficacy against pigmentedS. aureusNewman, Mu50 (vancomycin-intermediate MRSA, VISA), and NRS271 (linezolid-resistant MRSA, LRSA) comparable to that of linezolid and vancomycin in vivo.