Antibacterial activity and inhibition against Staphylococcus aureus NorA efflux pump by ferulic acid and its esterified derivatives

• Published in: Asian Pacific Journal of Tropical Biomedicine
• Main Authors: Patrícia Gonçalves Pinheiro, Gilvandete Maria Pinheiro Santiago, Francisco Erivaldo Freitas da Silva, Ana Carolina Justino de Araújo, Cícera Rejane Tavares de Oliveira, Priscilla Ramos Freitas, Janaína Esmeraldo Rocha, José Bezerra de Araújo Neto, Maria Milene Costa da Silva, Saulo Relison Tintino, Irwin Rose Alencar de Menezes, Henrique Douglas Melo Coutinho, José Galberto Martins da Costa
• Format: Article in Journal/Newspaper
• Language: English
• Published: Wolters Kluwer Medknow Publications 2021
• Subjects: ferulic acid; esterified derivatives; efflux pump; staphylococcus aureus; resistance mechanisms; Arctic medicine. Tropical medicine; RC955-962; Biology (General); QH301-705.5; Arctic
• Online Access: https://doi.org/10.4103/2221-1691.321130; https://doaj.org/article/63441b305a7e4163bc9d760e073de8e2

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.