Li Baoli, Ni Shuaishuai, Chen Feifei, Mao Fei, Wei Hanwen, Liu Yifu, Zhu Jin, Lan Lefu, Li Jian
Shanghai Key Laboratory of New Drug Design, School of Pharmacy , East China University of Science and Technology , 130 Meilong Road , Xuhui District, Shanghai , 200237 , China.
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica , Chinese Academy of Sciences , 646 Songtao Road , Pudong District, Shanghai , 201203 , China.
ACS Infect Dis. 2018 Mar 9;4(3):208-217. doi: 10.1021/acsinfecdis.7b00259. Epub 2018 Feb 12.
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, IC, of 16.1 μM) and 51 (hERG inhibition activity, IC > 40 μM) 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.
阻断金黄色葡萄球菌黄素的生物合成过程已成为一种有前景的抗毒力策略。我们之前的研究表明，去饱和八氢番茄红素脱氢酶是针对色素沉着金黄色葡萄球菌感染的一个有吸引力且可成药的靶点。苯并环烷衍生化合物是去饱和八氢番茄红素脱氢酶的有效抑制剂，但受限于高人类醚 - 去极化相关基因（hERG）抑制活性。在此，我们鉴定出一种新型含苯并七元环烷衍生物作为去饱和八氢番茄红素脱氢酶抑制剂。在58种类似物中，48号（hERG抑制活性，半数最大抑制浓度IC为16.1 μM）和51号（hERG抑制活性，IC>40 μM）因能有效抑制金黄色葡萄球菌纽曼菌株和三种耐甲氧西林金黄色葡萄球菌菌株的色素产生而脱颖而出，且这四种菌株对过氧化氢杀伤高度敏感，无杀菌生长效应。在体内试验中，48号和51号在小鼠肝脏和心脏中对金黄色葡萄球菌纽曼菌株的作用与利奈唑胺和万古霉素相当，正常给药时对Mu50和NRS271的作用更显著。
