盐酸白屈菜红碱逆转肺炎克雷伯菌中tmexCD1-toprJ1介导的高水平替加环素抗性
Chelerythrine chloride reverses high levels of tigecycline resistance mediated by tmexCD1-toprJ1 in Klebsiella pneumoniae
杨金典 1徐蕾 1吕冠辰 1崔民河 2朱先鹏 3邓旭明1
作者信息
- 1. 吉林大学动物医学学院,吉林 长春 130062
- 2. 吉林省牧硕养殖有限公司,吉林长春 130500
- 3. 吉林省柳河县农业综合行政执法大队,吉林通化 135300
- 折叠
摘要
通过棋盘试验、生长曲线试验、杀菌曲线试验、细菌膜通透性检测试验、外排泵功能检测试验、细胞毒性试验以及大蜡螟存活率试验等筛选出TMexCD1-TOprJ1外排泵抑制剂并验证其体内外替加环素协同抗菌活性.结果显示,白屈菜(Herba chelidonii)中活性成分盐酸白屈菜红碱显著提高替加环素的抗肺炎克雷伯菌(Klebsiella pneu-moniae,K.pneumoniae)活性(FICI≤0.5),通过与TMexC1/TMexD1/TOprJ1活性位点结合,抑制细菌外排泵的功能,同时增强替加环素对细菌膜的损伤,从而发挥与替加环素协同杀菌的作用;盐酸白屈菜红碱对J774A.1、Hep-2细胞无毒性作用.结果表明,盐酸白屈菜红碱作为一种新型替加环素增效剂具有抗击高致病性K.pneumoniae感染的潜力,为K.pneumoniae感染治疗提供了候选先导化合物.
Abstract
The aim of this study was to screen the TMexCD1-TOprJ1 efflux pump inhibitor and verify its synergistic antimicrobial activity of tigecycline in vivo and in vitro by using checkerboard assay,growth curve assay,time-killing assay,bacterial membrane permeability assay,efflux pump function assay,cytotoxicity assay,and survival rate of Galleria mellonella assay.The active ingre-dient in Herba chelidonii,chelerythrine chloride,significantly increased the anti-K.pneumoniae ac-tivity of tigecycline(FICI≤0.5),inhibited the function of the bacterial efflux pumps by binding to the active sites of TMexC1/TMexD1/TOprJ1,and enhanced the damage of tigecycline to bacterial membranes,thus exerting a synergistic effect with tigecycline.Chelerythrine chloride had no toxic effects on J774A.1 and Hep-2 cells.These findings reveal the potential of chelerythrine chloride as a novel tigecycline adjuvant against highly pathogenic K.pneumoniae infections and provide a can-didate lead compound for the treatment of K.pneumoniae infections.
关键词
盐酸白屈菜红碱/替加环素/TMexCD1-TOprJ1/协同活性/肺炎克雷伯菌Key words
chelerythrine chloride/tigecycline/TMexCD1-TOprJ1/synergistic activity/K.pneumoni-ae引用本文复制引用
基金项目
国家自然科学基金(U22A20523)
国家自然科学基金(32202856)
中国博士后科学基金(2023M731291)
出版年
2024
NETL
NSTL
万方数据