Insights into the molecular properties underlying antibacterial activity of prenylated (iso)flavonoids against MRSA

Abstract

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 (R2adj 0.61), low average prediction errors and a good predictive power (Q2) for the training (4% and Q2LOO 0.57, respectively) and the test set (5% and Q2test 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.

Valorisation of liquorice (Glycyrrhiza) roots: antimicrobial activity and cytotoxicity of prenylated (iso)flavonoids and chalcones from liquorice spent (G. glabra, G. inflata, and G. uralensis)

“…As the liquorice spent extracts are rich in prenylated phenolics, we propose that the extracts interact with the bacterial cytoplasmic membrane, thereby changing membrane fluidity, which can lead to membrane permeabilization, and bacterial cell death. 20,37,38…”

“…This might be explained by other potent antibacterial prenylated phenolics in our EtOAc spent extract of G. uralensis . For example, the double chain prenylated isoflavone 6,8-diprenylgenistein (4.2 ± 0.2 mg per g DW extract, Table H1, ESI†) has shown anti-MRSA activity with a MIC of 9 μg mL −1 , 37 and the double chain prenylated isoflavan licorisoflavan A (10.0 ± 0.6 mg per g DW extract, Table H1†) showed a MIC between 1–4 μg mL −1 against different species of S. mutans. 41 We cannot rule out that prenylated phenolics show synergistic effects with each other, as was shown by Chen and co-workers, 42 or with other minor or unknown compounds (small amounts of non-prenylated phenolics and triterpenoid aglycones were found in the liquorice spent extracts).…”

“…4 393 191 (72), 337 (100) 149(23), 161(16), 173(12), 177(10), 187(37), 189 (100), 201(32), 203(22), 295 (22),4 393 205 (13), 337 (100) 177 (27), 191 (16), 195 (52), 203 (17), 213 (100), 281 (19), 295 (22), 319 (63), 322 (27) 5 355 287 (100), 299 (70) 165 (13), 231 (11), 241 (14), 5 439 371 (47), 383 (100) 181 (100), 189 (86), 191 (20), 193 (15), 215 (12), 327 (58) R.A. = Relative abundance. a No = number corresponds to peaks in Fig.…”

Polyphenol and Tannin Nutraceuticals and Their Metabolites: How the Human Gut Microbiota Influences Their Properties

“…Regarding the antibacterial activity, isoflavones have shown inhibitory effects against biofilms of Escherichia coli and Listeria monocytogenes [ 47 ], as well as against MRSA [ 48 ]. Moreover, ingestion of isoflavones has been shown to potentially reduce viral infection and mortality of porcine reproductive and respiratory syndrome in pigs, with evident outcomes relevant to the food supply chain [ 49 ].…”

Millettia isoflavonoids: a comprehensive review of structural diversity, extraction, isolation, and pharmacological properties

“…Furthermore, many of the prenylated molecules are methoxylated, proving the structural diversity and complexity of Millettia isoflavones. Such structural diversity could provide an excellent opportunity for SAR research (Kalli et al 2021 ). Prenylation is thought to increase the lipophilic nature of organic molecules, which improves their affinity toward protein interactions in biological membranes (Botta et al 2009 ; Simons et al 2012 ; Veitch 2013 ).…”