Discovery of potent benzocycloalkane derived diapophytoene desaturase (CrtN) inhibitors with enhanced safety profile for the treatment of MRSA, VISA and LRSA infection
Discovery of potent benzocycloalkane derived diapophytoene desaturase (CrtN) inhibitors with enhanced safety profile for the treatment of MRSA, VISA and LRSA infection
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发现有效的苯并环烷衍生的二坡植物烯去饱和酶 (CrtN) 抑制剂，具有增强的安全性，可用于治疗 MRSA、VISA 和 LRSA 感染
DOI：
10.1021/acsinfecdis.7b00259
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发表时间：
2018
影响因子：
5.3
通讯作者：
Jian Li
中科院分区：
文献类型：
--
作者：
Baoli Li;Shuaishuai Ni;Feifei Chen;Fei Mao;Hanwen Wei;Yifu Liu;Jin Zhu;Lefu Lan;Jian Li
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 pigmentedStaphylococcus 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 μM) and51(hERG inhibition activity, IC50> 40 μM) were distinguished for effectively inhibiting the pigment production ofStaphylococcus aureusNewman and three methicillin-resistantStaphylococcus aureusstrains, and the four strains were highly sensitize to hydrogen peroxide killing without a bactericidal growth effect. In anin vivoassay,48and51displayed a comparable effect with linezolid and vancomycin in livers and hearts in mice againstStaphylococcus aureusNewman and a more considerable effect against Mu50 and NRS271 with normal administration.
