Abstract
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.
Highlights
Interest in natural compounds for antimicrobial discovery has increased during the last decade due to the rise in highly resistant bacteria[1]
When the efflux pumps were inhibited by PAβN, E. coli became susceptible to a similar extent as L. monocytogenes
Not all prenylatedflavonoids tested in this study showed potent antibacterial activity, suggesting that increase of hydrophobicity by prenylation alone does not warrant antibacterial activity and that structural details might have a profound effect on antibacterial potency
Summary
Interest in natural compounds for antimicrobial discovery has increased during the last decade due to the rise in highly resistant bacteria[1]. These phenolic compounds mainly belong to the flavonoid (2-phenyl benzopyrans), isoflavonoid (3-phenyl benzopyrans) and stilbenoid (1,2-diphenyl ethylene) classes Besides the skeleton, they can differ in configuration and position of prenylation. We tested 30 mono- and diprenylated (iso)flavonoids (Fig. 1), belonging to 6 different (iso)flavonoid subclasses, prenylated at different positions of the main skeleton and with chain, pyran or furan prenyl configurations. The majority of these molecules has never been tested before against L. monocytogenes, or against E. coli in the presence of an efflux pump
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