Abstract：
Herein, we report the hit-to-lead identification of a drug-like pleuromutilin conjugate 16, based on a triaromatic hit reported in 2020. The lead arose as the clear candidate from a hit-optimization campaign in which Gram-positive antibacterial activity, solubility, and P-gp affinity were optimized. Conjugate 16 was extensively evaluated for its in vitro ADMET performance which, apart from solubility, was overall on par with lefamulin. This evaluation included Caco-2 cell permeability, plasma protein binding, hERG inhibition, cytotoxicity, metabolism in microsomes and CYP3A4, resistance induction, and time-kill kinetics. Intravenous pharmacokinetics of 16 proved satisfactory in both mice and pigs; however, oral bioavailability was limited likely due to insufficient solubility. The in vivo efficacy was evaluated in mice, systemically infected with Staphylococcus aureus, where 16 showed rapid reduction in blood bacteriaemia. Through our comprehensive studies, lead 16 has emerged as a highly promising and safe antibiotic candidate for the treatment of Gram-positive bacterial infections.
摘要：
在这里，我们报告了基于2020年报告的三芳香化合物命中的药物样截短侧耳素缀合物16的命中-铅鉴定。在革兰氏阳性抗菌活性的热门优化运动中，铅作为明确的候选者出现，溶解度，优化P-gp亲和力。对缀合物16的体外ADMET性能进行了广泛评估，除了溶解度，总体上与lefamulin相当。该评估包括Caco-2细胞通透性，血浆蛋白结合，hERG抑制，细胞毒性，微粒体和CYP3A4的代谢，抗性诱导，和时间杀死动力学。16的静脉药代动力学证明在小鼠和猪中都令人满意；然而，口服生物利用度有限,可能是由于溶解度不足.在小鼠中评估体内功效，金黄色葡萄球菌全身感染，其中16显示血液菌血症迅速减少。通过我们的全面研究，铅16已成为治疗革兰氏阳性细菌感染的非常有前途和安全的候选抗生素。
