Mechanistic study of the antibacterial potential of the prenylated flavonoid auriculasin against Escherichia coli

Abstract

Bacterial resistance is spreading in an alarming manner, outpacing the rate of development of new antibacterial agents and surging the need for effective alternatives.Prenylated flavonoids are a promising class of natural antibiotics with reported activity against a wide range of resistant pathogens. Here, a large library of natural flavonoids (1718 structures) was virtually screened for potential candidates inhibiting the B-subunit of gyrase (Gyr-B). Twenty-eight candidates, predominated by prenylated flavonoids, appeared as promising hits. Six of them were selected for further in vitro antibacterial and Gyr-B enzyme inhibitory activities. Auriculasin is presented as the most potent antibacterial candidate, with a MIC ranging from 2 to 4 µg/ml against two clinically isolated multidrug-resistant Escherichia coli strains. Mechanistic antibacterial analysis revealed auriculasin inhibitory activity towards the Gyr-B enzyme on the micromolar scale (IC 50 = 0.38 ± 0.15 µM). Gyr-B interaction was further detailed by conducting an isothermal titration calorimetric experiment, which revealed a competitive inhibition with a high affinity for the Gyr-B active site, achieved mostly through enthalpic interactions (ΔG binding = −10.69 kcal/mol). Molecular modeling and physics-based simulations demonstrated the molecule's manner of fitting inside the Gyr-B active site, indicating a very potential nucleus for the future generation of more potent derivatives. To conclude, prenylated flavonoids are interesting antibacterial candidates with anti-Gyr-B mechanism of action that can be obtained from a plant-derived flavonoid.

Antimicrobial Quantitative Relationship and Mechanism of Plant Flavonoids to Gram-Positive Bacteria

“…Recently, many antimicrobial mechanisms and SARs of plant flavonoids against Gram-negative bacteria have been reported [ 17 , 40 , 41 ]. As this research focused on the antimicrobial quantitative relationships and mechanisms of the plant flavonoids against Gram-positive bacteria, those of the plant flavonoids against Gram-negative bacteria were not discussed here.…”

Bio-fabricated zinc oxide nanoparticles mediated by endophytic fungus Aspergillus sp. SA17 with antimicrobial and anticancer activities: in vitro supported by in silico studies

“…Moreover, modeling and MD simulation results suggest that glabrol and pomiferin in the tested extract are the antibacterial-relevant metabolites, while daidzein 4′-sulfate is the anticancer-relevant metabolite. In previous reports, glabrol and pomiferin have been shown to exert interesting antibacterial efficacies vs. both Gram-positive and Gram-negative pathogenic bacteria including antibiotics-resistant ones ( Gerhäuser, 2005 ; Stompor and Żarowska, 2016 ; Wu et al, 2019 ; Mohamed et al, 2022 ).…”

Blackberry-Loaded AgNPs Attenuate Hepatic Ischemia/Reperfusion Injury via PI3K/Akt/mTOR Pathway

“…Previous report for calculating the binding free energy (Δ G ) and performing molecular dynamic simulations were followed [ 54 ]. These procedures are described in detail in the Supplementary File .…”