Laboratory of Food Chemistry, Wageningen University and Research, Bornse Weilanden 9, 6708 WG, Wageningen, The Netherlands.
Laboratory of Microbiology and Biotechnology, Faculty of Pharmacy, Universitas Indonesia, Depok, 16424, Indonesia.
Sci Rep. 2023 Dec 18;13(1):22548. doi: 10.1038/s41598-023-48992-8.
Overexpression of NorA efflux pumps plays a pivotal role in the multidrug-resistance mechanism in S. aureus. Here, we investigated the activities of prenylated isoflavonoids, present in the legume plant family (Fabaceae), as natural efflux pump inhibitors (EPIs) in fluoroquinolone-resistant S. aureus. We found that four prenylated isoflavonoids, namely neobavaisoflavone, glabrene, glyceollin I, and glyceollin III, showed efflux pump inhibition in the norA overexpressing S. aureus. At sub-inhibitory concentrations, neobavaisoflavone (6.25 µg/mL, 19 µM) and glabrene (12.5 µg/mL, 39 µM), showed up to 6 times more Eth accumulation in norA overexpressing S. aureus than in the control. In addition, these two compounds boosted the MIC of fluoroquinolones up to eightfold. No fluoroquinolone potentiation was observed with these isoflavonoids in the norA knockout strain, indicating NorA as the main target of these potential EPIs. In comparison to the reported NorA EPI reserpine, neobavaisoflavone showed similar potentiation of fluoroquinolone activity at 10 µM, higher Eth accumulation, and less cytotoxicity. Neobavaisoflavone and glabrene did not exhibit membrane permeabilization effects or cytotoxicity on Caco-2 cells. In conclusion, our findings suggest that the prenylated isoflavonoids neobavaisoflavone and glabrene are promising phytochemicals that could be developed as antimicrobials and resistance-modifying agents to treat fluoroquinolone-resistant S. aureus strains.
NorA 外排泵的过度表达在金黄色葡萄球菌的多药耐药机制中起着关键作用。在这里，我们研究了豆科植物（Fabaceae）中存在的类异戊二烯黄酮作为氟喹诺酮耐药金黄色葡萄球菌天然外排泵抑制剂 (EPI) 的活性。我们发现，四种类异戊二烯黄酮，即新巴西黄酮、甘草素、大豆苷元和大豆苷元 III，在 norA 过表达的金黄色葡萄球菌中表现出外排泵抑制作用。在亚抑制浓度下，新巴西黄酮（6.25 µg/mL，19 µM）和甘草素（12.5 µg/mL，39 µM）在 norA 过表达的金黄色葡萄球菌中的 Eth 积累量比对照高出 6 倍。此外，这两种化合物将氟喹诺酮的 MIC 提高了 8 倍。在 norA 敲除株中，这些化合物没有表现出氟喹诺酮的增效作用，表明 NorA 是这些潜在 EPI 的主要靶标。与报道的 NorA EPI 利血平相比，新巴西黄酮在 10 µM 时显示出相似的氟喹诺酮活性增强作用，Eth 积累更高，细胞毒性更小。新巴西黄酮和甘草素在 Caco-2 细胞上没有表现出膜通透性作用或细胞毒性。总之，我们的研究结果表明，类异戊二烯黄酮新巴西黄酮和甘草素是有前途的植物化学物质，可以开发为治疗氟喹诺酮耐药金黄色葡萄球菌的抗菌和耐药修饰剂。
