Laboratory of Food Chemistry, Wageningen University & Research, Wageningen, The Netherlands.
Biometris, Applied Statistics, Wageningen University & Research, Wageningen, The Netherlands.
Sci Rep. 2021 Jul 9;11(1):14180. doi: 10.1038/s41598-021-92964-9.
High resistance towards traditional antibiotics has urged the development of new, natural therapeutics against methicillin-resistant Staphylococcus aureus (MRSA). Prenylated (iso)flavonoids, present mainly in the Fabaceae, can serve as promising candidates. Herein, the anti-MRSA properties of 23 prenylated (iso)flavonoids were assessed in-vitro. The di-prenylated (iso)flavonoids, glabrol (flavanone) and 6,8-diprenyl genistein (isoflavone), together with the mono-prenylated, 4'-O-methyl glabridin (isoflavan), were the most active anti-MRSA compounds (Minimum Inhibitory Concentrations (MIC) ≤ 10 µg/mL, 30 µM). The in-house activity data was complemented with literature data to yield an extended, curated dataset of 67 molecules for the development of robust in-silico prediction models. A QSAR model having a good fit (R 0.61), low average prediction errors and a good predictive power (Q) for the training (4% and Q 0.57, respectively) and the test set (5% and Q 0.75, respectively) was obtained. Furthermore, the model predicted well the activity of an external validation set (on average 5% prediction errors), as well as the level of activity (low, moderate, high) of prenylated (iso)flavonoids against other Gram-positive bacteria. For the first time, the importance of formal charge, besides hydrophobic volume and hydrogen-bonding, in the anti-MRSA activity was highlighted, thereby suggesting potentially different modes of action of the different prenylated (iso)flavonoids.
高抗药性传统抗生素促使人们开发新的天然疗法来对抗耐甲氧西林金黄色葡萄球菌 (MRSA)。存在于豆科植物中的被普烯基化（异）黄酮，可以作为有前途的候选药物。在此，评估了 23 种被普烯基化（异）黄酮的体外抗 MRSA 特性。二普烯基化（异）黄酮，即芒柄花素（flavanone）和 6,8-二普烯基染料木素（异黄酮），以及单普烯基化的 4'-O-甲基甘草素（isoflavan），是最有效的抗 MRSA 化合物（最低抑菌浓度 (MIC)≤10 µg/mL，30 µM）。内部活性数据与文献数据相结合，为开发稳健的计算预测模型提供了扩展的、经过整理的 67 种分子数据集。得到了一个具有良好拟合度（R 0.61）、低平均预测误差和良好预测能力（Q 分别为训练集的 0.57 和 0.75）的 QSAR 模型。此外，该模型还很好地预测了外部验证集的活性（平均预测误差为 5%），以及普烯基化（异）黄酮对其他革兰氏阳性菌的活性水平（低、中、高）。首次强调了形式电荷（除了疏水性体积和氢键）在抗 MRSA 活性中的重要性，从而表明不同的普烯基化（异）黄酮可能具有不同的作用模式。
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