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 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.

Systematic analysis of bacteriostatic mechanism of flavonoids using transcriptome and its therapeutic effect on vaginitis

“…In addition, we detected that the DNA and RNA exudations of S. aureus, E. coli and P. aeruginosa were also remarkably enhanced after the administration of flavonoids in A. conyzoides for 2 hours. There have been several evidences showed that flavonoids could exert their antibacterial actions via inducing membrane permeabilization [14][15][16]. Hence, we speculate that the antibacterial mechanism of flavonoids in A. conyzoides is that they can also cause membrane permeabilization and consequent nucleic acid exudation in bacteria.…”

Effects of the Licorice Isoflavans Licoricidin and Glabridin on the Growth, Adherence Properties, and Acid Production of Streptococcus mutans, and Assessment of Their Biocompatibility

“…In previous studies, licoricidin has been reported to exert antibacterial activity against Porphyromonas gingivalis and Prevotella intermedia, two periodontal pathogens [ 21 ] as well as against the endodontic pathogen Enterococcus faecalis [ 22 ]. Although we did not investigate the mechanism of antibacterial action of the isoflavans tested, a previous study by Araya-Cloutier et al [ 23 ] showed that glabridin causes membrane permeabilization as determined by the uptake of the fluorescent probe propidium iodide. Other flavonoids isolated from licorice root, including 1-methoxyficifolinol, 6,8-diprenylgenistein, 6,8-diisoprenyl-5,7,4′-trihydroxyflavone, gancaonin G, glycyrrhizol A, glycyrrhizol B, and licorisoflavan A have also been reported to exhibit antibacterial activity against S. mutans [ 17 , 24 ].…”

Identification of Novel Antibacterials Using Machine Learning Techniques

“…It should be especially noted that several of the selected molecular descriptors were described previously as important for statistically significant separation between antibacterial and nonantibacterial compounds (Araya-Cloutier et al, 2018). Distributions for the representative descriptors used for learning herein are depicted in Figure 1 .…”