Prenylated flavonoids and isoflavonoids are phytochemicals with remarkable antibacterial activity. In this study, 30 prenylated (iso)flavonoids were tested against Listeria monocytogenes and Escherichia coli (the latter in combination with an efflux pump inhibitor). Minimum inhibitory concentrations of the most active compounds ranged between 6.3–15.0 µg/mL. Quantitative structure-activity relationships (QSAR) analysis was performed and linear regression models were proposed with R2 between 0.77–0.80, average R2m between 0.70–0.75, Q2LOO between 0.66–0.69, and relatively low amount of descriptors. Shape descriptors (related to flexibility and globularity), together with hydrophilic/hydrophobic volume and surface area descriptors, were identified as important molecular characteristics related to activity. A 3D pharmacophore model explaining the effect of the prenyl position on the activity of compounds was developed for each bacterium. These models predicted active compounds with an accuracy of 71–88%. With regard to the mode of action, good antibacterial prenylated (iso)flavonoids with low relative hydrophobic surface area caused remarkable membrane permeabilization, whereas those with higher relative hydrophobic surface area did not. Based on the QSAR and membrane permeabilization studies, the mode of action of antibacterial prenylated (iso)flavonoids was putatively rationalized.
Prenylated flavonoids possess a wide
variety of biological activities,
including estrogenic, antioxidant, antimicrobial, and anticancer activities.
Hence, they have potential applications in food products, medicines,
or supplements with health-promoting activities. However, the low
abundance of prenylated flavonoids in nature is limiting their exploitation.
Therefore, we investigated the prospect of producing prenylated flavonoids
in the yeast Saccharomyces cerevisiae. As a proof of concept, we focused on the production of the potent
phytoestrogen 8-prenylnaringenin. Introduction of the flavonoid prenyltransferase
SfFPT from Sophora flavescens in naringenin-producing
yeast strains resulted in de novo production of 8-prenylnaringenin.
We generated several strains with increased production of the intermediate
precursor naringenin, which finally resulted in a production of 0.12
mg L–1 (0.35 μM) 8-prenylnaringenin under
shake flask conditions. A number of bottlenecks in prenylated flavonoid
production were identified and are discussed.
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.
A new
method to simultaneously
analyze various glucosinolates (GSLs) and isothiocyanates (ITCs) by
reversed-phase ultra-high-performance liquid chromatography–electron
spray ionization–tandem mass spectrometry has been developed
and validated for 14 GSLs and 15 ITCs. It involved derivatization
of ITCs with N-acetyl-l-cysteine (NAC).
The limits of detection were 0.4–1.6 μM for GSLs and
0.9–2.6 μM for NAC–ITCs. The analysis of Sinapis alba, Brassica napus, and Brassica juncea extracts spiked
with 14 GSLs and 15 ITCs indicated that the method generally had good
intraday (≤10% RSD) and interday precisions (≤16% RSD).
Recovery of the method was unaffected by the extracts and within 71–110%
for GSLs and 66–122% for NAC–ITCs. The method was able
to monitor the enzymatic hydrolysis of standard GSLs to ITCs in mixtures.
Furthermore, GSLs and ITCs were simultaneously determined in Brassicaceae
plant extracts before and after myrosinase treatment. This method
can be applied to further investigate the enzymatic conversion of
GSLs to ITCs in complex mixtures.
Glucosinolates (GSLs) are of interest
for potential antimicrobial
activity of their degradation products and exclusive presence in Brassicaceae.
Compositional changes of aliphatic, benzenic, and indolic GSLs of Sinapis alba, Brassica napus, and B. juncea seeds by germination and fungal elicitation were
studied. Rhizopus oryzae (nonpathogenic), Fusarium graminearum (nonpathogenic), and F. oxysporum (pathogenic) were employed. Thirty-one GSLs were detected by reversed-phase
ultrahigh-performance liquid chromatography photodiode array with
in-line electrospray ionization mass spectrometry (RP-UHPLC-PDA-ESI-MSn). Aromatic-acylated derivatives of 3-butenyl GSL, p-hydroxybenzyl GSL, and indol-3-ylmethyl GSL were for the
first time tentatively annotated and confirmed to be not artifacts.
For S. alba, germination, Rhizopus elicitation, and F. graminearum elicitation increased
total GSL content, mainly consisting of p-hydroxybenzyl
GSL, by 2–3 fold. For B. napus and B. juncea, total GSL content was unaffected by germination
or elicitation. In all treatments, aliphatic GSL content was decreased
(≥50%) in B. napus and remained unchanged
in B. juncea. Indolic GSLs were induced in all species
by germination and nonpathogenic elicitation.
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