Zhou Yonglin, Guo Yan, Wen Zhongmei, Ci Xinxin, Xia Lining, Wang Yanling, Deng Xuming, Wang Jianfeng
Department of Respiratory Medicine, the First Hospital of Jilin University, Changchun 130021, China.
Key Laboratory of Zoonosis Research, Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun 130062, China.
Pathogens. 2020 Feb 26;9(3):161. doi: 10.3390/pathogens9030161.
β-Lactamase-positive is one of the most prevalent multidrug-resistant pathogens worldwide and is associated with increasing threats to clinical therapeutics and public health. Here, we showed that isoalantolactone (IAL), in combination with penicillin G, exhibited significant synergism against 21 β-lactamase-positive strains (including methicillin resistant ). An enzyme inhibition assay, a checkerboard minimum inhibitory concentration (MIC) assay, a growth curve assay, a time-killing assay, a RT-PCR assay and Circular Dichroism (CD) spectroscopy were performed on different β-lactamases or β-lactamase-positive strains, in vitro, to confirm the mechanism of inhibition of β-lactamase and the synergistic effects of the combination of penicillin G and IAL. All the fractional inhibitory concentration (FIC) indices of penicillin G, in combination with IAL, against β-lactamase-positive were less than 0.5, and ranged from 0.10 ± 0.02 to 0.38 ± 0.17. The survival rate of -infected mice increased significantly from 35.29% to 88.24% within 144 h following multiple compound therapy approaches. Unlike sulbactam, IAL inactivated β-lactamase during protein translation, and the therapeutic effect of combination therapy with IAL and penicillin G was equivalent to that of sulbactam with penicillin G. Collectively, our results indicated that IAL is a promising and leading drug that can be used to restore the antibacterial effect of β-lactam antibiotics such as penicillin G and to address the inevitable infection caused by βlactamase-positive .
β-内酰胺酶阳性菌是全球最普遍的多重耐药病原体之一，对临床治疗和公共卫生构成日益严重的威胁。在此，我们发现异土木香内酯（IAL）与青霉素G联合使用时，对21株β-内酰胺酶阳性菌（包括耐甲氧西林菌）表现出显著的协同作用。我们对不同的β-内酰胺酶或β-内酰胺酶阳性菌进行了酶抑制试验、棋盘式最低抑菌浓度（MIC）试验、生长曲线试验、杀菌试验、逆转录聚合酶链反应（RT-PCR）试验和圆二色性（CD）光谱分析，以确认IAL对β-内酰胺酶的抑制机制以及青霉素G与IAL联合使用的协同效应。青霉素G与IAL联合使用对β-内酰胺酶阳性菌的所有部分抑菌浓度（FIC）指数均小于0.5，范围为0.10±0.02至0.38±0.17。在采用多种联合治疗方法后的144小时内，感染小鼠的存活率从35.29%显著提高到88.24%。与舒巴坦不同，IAL在蛋白质翻译过程中使β-内酰胺酶失活，IAL与青霉素G联合治疗的效果与舒巴坦与青霉素G联合治疗的效果相当。总体而言，我们的结果表明IAL是一种有前景的先导药物，可用于恢复青霉素G等β-内酰胺类抗生素的抗菌效果，并应对由β-内酰胺酶阳性菌引起的不可避免的感染。
