No abstract

Objective: To evaluate the inhibitory activity of ferulic acid and four of its esterified derivatives (methyl, ethyl, propyl, and butyl) against resistance mechanisms in Staphylococcus aureus strains. Methods: Ferulic acid derivatives were obtained by esterification with methanol, ethanol, propanol, and butanol, and then characterized by hydrogen and carbon-13 nuclear magnetic resonance analysis. The minimum inhibitory concentrations (MIC) of ferulic acid and its esterified derivatives, ethidium bromide, and norfloxacin were obtained using the microdilution test, while the efflux pump inhibition test was conducted by examining reduction in the MICs of norfloxacin and ethidium bromide. Molecular docking was also carried out using the Schrodinger Suite 2015 molecular modeling software. A three-dimensional model of NorA efflux pump was generated using I-TASSER. The best scoring model was used as a receptor for ligand-receptor docking. Results: The methyl and butyl ester derivatives did not demonstrate significant antimicrobial activity. However, a significant synergic effect was evidenced when norfloxacin was combined with the ethyl and propyl esterified derivatives. The docking study demonstrated favorable energy of interaction between ferulate derivatives and NorA, and amino acid residues TYR57, TYR58, and LEU255 were present commonly in stabilizing all complexes. The PCA analysis corroborated the docking hypothesis that the lipophilic character and hydrogen bond interactions were the most relevant characteristics involved with NorA inhibitors. The pharmacokinetic parameters of ferulic acid derivatives showed good ADMET properties, demonstrating that they can be easily absorbed and have no effect or inhibit the cytochrome P450 enzyme complex, revealing their potential as drug candidates. Conclusions: This study provides strong evidence that the molecular basis for this activity is potentially due to the NorA efflux pump.

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In this study, twelve campesterol derivatives (2-13) were prepared by esterification reaction at the hydroxy group in C-3 and catalytic hydrogenation at the carbon-carbon double bond in C-5(6). All obtained compounds were characterized by IR, 1 H-NMR, 13 C-NMR, and MS spectra. Campesterol (1) and its derivatives (2-13) were evaluated in vitro against Staphylococcus aureus (ATCC 6538), Streptococcus mutans (ATCC 0046), Escherichia coli (ATCC 10536), Pseudomonas aeruginosa (ATCC 15442), and Klebsiella pneumoniae (ATCC 10031) using the microdilution method. Among tested compounds, 4, 6, 9, 11, 12, and 13 displayed the best antibacterial activity. Moreover, to support the antibacterial activity experiments, the investigation of molecular interactions of more active compounds, and also compound 1 and neomycin, used as starting material and positive control, respectively, at the binding site of the target proteins was performed using molecular docking simulations. Four compounds (7, 9, 10 and 11) are herein described for the first time.