【作者】 杨元帅； 卢曦； 游雪甫； 宋丹青；

【Author】 Yang Yuan-shuai;Lu Xi;You Xue-fu;Song Dan-qing;Institute of Medicinal Biotechnology.Chinese Academy of Medical Sciences and Peking Union Medical College;

【机构】 中国医学科学院医药生物技术研究所；

【摘要】 目的:基于临床使用β-内酰胺酶抑制剂—舒巴坦还具有独特的抗鲍曼不动杆菌活性,寻找抗鲍曼不动杆菌候选物。方法:以6-氨基青霉烷酸为起始原料设计合成一系列青霉烷类衍生物,评价其体外抗菌活性,阐明构效关系,对活性较好的化合物进一步开展成药性评价。结果:20个目标化合物中,化合物7对鲍曼不动杆菌表现出与对照药舒巴坦有相当的抑菌活性,MIC为1μg/mL。同舒巴坦相比,化合物7显示出较好的药代动力学性质,口服给药最大血药浓度C_max为舒巴坦的60倍左右,达峰时间快,半衰期为舒巴坦的4倍左右,口服吸收良好。初步研究推测,化合物7为水溶性小分子,可能通过独特的药物通道CarO进入菌体内发挥抗鲍曼不动杆菌的活性。结论:化合物7发挥了较好的抗鲍曼不动杆菌活性,且口服吸收良好,值得进一步研究。更多还原

【Abstract】 Objective To obtain the potential candidates with unique chemical structure and novel mechanism against Acinetobacter baumannii.Methods A series of new penam derivatives were synthesized from 6-aminopenicillnic acid and evaluated the in vitro antibacterial activities.Pharmacokinetics test of the compounds with better activity in rat was studied.Results 20 target compounds were prepared,and compound 7 showed excellent in vitro anti-baumannii activity with low minimum inhibitory concentration（MIC） values of 1μg/mL.Moreover,compound 7 displayed a better pharmacokinetic properties(C_max=19567 ng/mL,approximately 60 times than that of sulbactam),which illustrated that oral absorption of compound 7 was better.Compound 7 and sulabactam might enter Acinetobacter baumannii via outer membrane protein CarO,and then exerted the antibacterial function.Conclusion A penam derivatives library against Acinetobacter baumannii was constructed.Compound 7 with good anti-baumannii activity and excellent pharmacokinetic properties deserves a further study.更多还原