QSAR-based molecular signatures of prenylated (iso)flavonoids underlying antimicrobial potency against and membrane-disruption in Gram positive and Gram negative bacteria

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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 R2 m between 0.70-0.75, Q2 LOO 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.

LanguageEnglish
Article number9267
JournalScientific Reports
Volume8
DOIs
Publication statusPublished - 18 Dec 2018

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Quantitative Structure-Activity Relationship
Gram-Negative Bacteria
Flavonoids
Membranes
Linear Models
Listeria monocytogenes
Phytochemicals
Microbial Sensitivity Tests
Escherichia coli
Bacteria

Cite this

@article{d5b0debd63a44e71a344b7d593feef1e,
title = "QSAR-based molecular signatures of prenylated (iso)flavonoids underlying antimicrobial potency against and membrane-disruption in Gram positive and Gram negative bacteria",
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 R2 m between 0.70-0.75, Q2 LOO 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.",
author = "Carla Araya-Cloutier and Vincken, {Jean Paul} and {van de Schans}, {Milou G.M.} and Jos Hageman and Gijs Schaftenaar and {den Besten}, {Heidy M.W.} and Harry Gruppen",
year = "2018",
month = "12",
day = "18",
doi = "10.1038/s41598-018-27545-4",
language = "English",
volume = "8",
journal = "Scientific Reports",
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publisher = "Nature Publishing Group",

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T1 - QSAR-based molecular signatures of prenylated (iso)flavonoids underlying antimicrobial potency against and membrane-disruption in Gram positive and Gram negative bacteria

AU - Araya-Cloutier, Carla

AU - Vincken, Jean Paul

AU - van de Schans, Milou G.M.

AU - Hageman, Jos

AU - Schaftenaar, Gijs

AU - den Besten, Heidy M.W.

AU - Gruppen, Harry

PY - 2018/12/18

Y1 - 2018/12/18

N2 - 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 R2 m between 0.70-0.75, Q2 LOO 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.

AB - 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 R2 m between 0.70-0.75, Q2 LOO 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.

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