Beijing Key Laboratory of Antimicrobial Agents, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China; Division for Medicinal Microorganisms Related Strains, CAMS Collection Center of Pathogenic Microorganisms, Beijing 100050, China.
Beijing Key Laboratory of Antimicrobial Agents, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
Phytomedicine. 2024 Jun;128:155400. doi: 10.1016/j.phymed.2024.155400. Epub 2024 Feb 1.
The emergence and spread of vancomycin-resistant enterococci (VRE) have posed a significant challenge to clinical treatment, underscoring the need to develop novel strategies. As therapeutic options for VRE are limited, discovering vancomycin enhancer is a feasible way of combating VRE. Gambogic acid (GA) is a natural product derived from the resin of Garcinia hanburyi Hook.f. (Clusiaceae), which possesses antibacterial activity.
This study aimed to investigate the potential of GA as an adjuvant to restore the susceptibility of VRE to vancomycin.
In vitro antibacterial and synergistic activities were evaluated against vancomycin-susceptible and resistant strains by the broth microdilution method for the Minimal Inhibitory Concentrations (MICs) determination, and checkerboard assay and time-kill curve analysis for synergy evaluation. In vivo study was conducted on a mouse multi-organ infection model. The underlying antibacterial mechanism of GA was also explored.
GA showed a potent in vitro activity against all tested strains, with MICs ranging from 2 to 4 μg/ml. The combination of GA and vancomycin exhibited a synergistic effect against 18 out of 23 tested VRE strains, with a median fractional inhibitory concentration index (FICI) of 0.254, and demonstrated a synergistic effect in the time-kill assay. The combination therapy exhibited a significant reduction in tissue bacterial load compared with either compound used alone. GA strongly binds to the ParE subunit of topoisomerase IV, a bacterial type II DNA topoisomerase, and suppresses its activity.
The study suggests that GA has a significant antibacterial activity against enterococci, and sub-MIC concentrations of GA can restore the activity of vancomycin against VRE in vitro and in vivo. These findings indicate that GA has the potential to be a new antibacterial adjuvant to vancomycin in the treatment of infections caused by VRE.
耐万古霉素肠球菌（VRE）的出现和传播对临床治疗构成了重大挑战，这凸显了开发新策略的必要性。由于 VRE 的治疗选择有限，因此发现万古霉素增强剂是对抗 VRE 的一种可行方法。藤黄酸（GA）是从藤黄（藤黄科）树脂中提取的天然产物，具有抗菌活性。
本研究旨在探讨 GA 作为增强剂恢复 VRE 对万古霉素敏感性的潜力。
采用肉汤微量稀释法测定最小抑菌浓度（MIC），棋盘试验和时间杀伤曲线分析评估 GA 对万古霉素敏感和耐药株的体外抗菌和协同活性。在小鼠多器官感染模型中进行了体内研究。还探讨了 GA 的潜在抗菌机制。
GA 对所有测试菌株均表现出强大的体外活性，MIC 范围为 2 至 4 μg/ml。GA 与万古霉素联合使用对 23 株测试 VRE 菌株中的 18 株表现出协同作用，中位部分抑菌浓度指数（FICI）为 0.254，并且在时间杀伤试验中表现出协同作用。与单独使用任一化合物相比，联合治疗可显著降低组织细菌负荷。GA 可与拓扑异构酶 IV 的 ParE 亚基强烈结合，拓扑异构酶 IV 是一种细菌 II 型 DNA 拓扑异构酶，并抑制其活性。
该研究表明，GA 对肠球菌具有显著的抗菌活性，亚 MIC 浓度的 GA 可在体外和体内恢复万古霉素对 VRE 的活性。这些发现表明，GA 有可能成为治疗 VRE 感染的万古霉素的新型抗菌佐剂。
