A novel series of steroidal β-carboline quaternary ammonium derivatives (SCQADs) derived from natural cholic acid and its derivatives was designed, synthesized and biologically evaluated against four Gram-positive bacteria for the first time. Most of these derivatives exhibited promising antibacterial activity against the tested strains, particularly, compound 21g displayed strong antibacterial activity against MRSA (MIC = 0.5 – 1 μg/mL) with low cytotoxicity. Meanwhile, derivative 21g was able to quickly kill Gram-positive bacteria within 0.5 h without inducing bacterial resistance. Preliminary mechanistic explorations indicated that compound 21g destroyed bacterial cell membranes to exert its antibacterial effects. Moreover, 21g exhibited high in vivo efficacy and high survival protection in a mouse skin abscess model. These findings suggested that compound 21g has great potential to develop as an antibacterial agent.

中文翻译：

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新型甾体 β-Carboline 衍生物作为对抗耐甲氧西林金黄色葡萄球菌的有前途的抗菌候选者


设计、合成了一系列源自天然胆酸及其衍生物的新型甾体 β-咔啉季铵衍生物 （SCQADs），并首次针对四种革兰氏阳性菌进行了生物学评价。这些衍生物中的大多数对供试菌株表现出有希望的抗菌活性，特别是化合物 21g 对 MRSA 表现出很强的抗菌活性 （MIC = 0.5 – 1 μg/mL），细胞毒性低。同时，衍生物 21g 能够在 0.5 h 内快速杀死革兰氏阳性菌，而不会诱导细菌耐药。初步机制探索表明，化合物 21g 破坏细菌细胞膜以发挥其抗菌作用。此外，21g 在小鼠皮肤脓肿模型中表现出高体内疗效和高生存保护。这些发现表明化合物 21g 作为抗菌剂具有很大的潜力。