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 μM) and 51 (hERG inhibition activity, IC₅₀ > 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.

中文翻译：

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发现具有增强的安全性的强苯并环烷烃衍生的双卟啉去饱和酶抑制剂，用于治疗MRSA，VISA和LRSA感染

阻止葡萄黄素的生物合成过程已成为一种有前途的抗毒策略。我们以前的研究表明，二po烯脱氢酶是一种有吸引力的可药物治疗的目标，可以预防由有色葡萄球菌引起的感染。苯并环烷烃衍生的化合物是有效的二氮杂卟啉去饱和酶抑制剂，但受到高hERG（人类以太相关基因）抑制活性的限制。在这里，我们确定了一种新型的含苯并庚烷的环烷烃衍生物作为二苯并to烯去饱和酶抑制剂。在58个类似物中，48个（hERG抑制活性，最大抑制浓度的一半，IC ₅₀为16.1μM）和51个（hERG抑制活性，IC _50，）> 40μM）可有效抑制金黄色葡萄球菌Newman和3株耐甲氧西林的金黄色葡萄球菌菌株的产生，并且这4株菌株对过氧化氢的杀灭高度敏感，而没有杀菌作用。在体内试验中，48和51在小鼠肝脏和心脏中对利奈唑胺和万古霉素具有抗金黄色葡萄球菌纽曼的作用，在正常给药下对Mu50和NRS271具有更显着的作用。