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<p>The advancement of Antimicrobial Resistance (AMR) and the lack of effective treatments demand the development of new drugs to combat resistant bacteria. Plants, in turn, produce various Secondary Metabolites (SMs) with diverse molecular structures, which are promising therapeutic alternatives. This study aims to evaluate the potential of 13 plant derived SMs in modulating bacterial resistance to amoxicillin (AMO), and to investigate the mechanisms of action against <i>Staphylococcus aureus</i> (ATCC 29213) and <i>Klebsiella pneumoniae</i> (UFPDA 396) using Molecular Docking (MD) simulations. Among the tested SMs, <i>p</i>-Cymene (CYM) showed the best activity against <i>S. aureus</i>, with a Minimum Inhibitory Concentration (MIC) of 512&#xa0;µg/mL, while Eugenol (EUG) was most effective against <i>K. pneumoniae</i>, with an MIC of 1024&#xa0;µg/mL. In resistance modulation assays using the checkerboard method, SMs including EUG, CYM, α-pinene (APN), β-pinene (BPN), Geraniol (GER), Linalool (LNL), and Myrcene (MYR) exhibited synergistic effects when combined with AMO, with Fractional Inhibitory Concentration Index (FICI) values ranging from 0.1 to 0.5. Additionally, both the SMs and AMO, as well as their synergistic combinations, were docked to molecular targets associated with resistance and virulence in <i>S. aureus</i> and <i>K. pneumoniae</i>. The drug–protein complexes showed favorable interaction energies, confirming that the binding free energy of the synergistic combinations was superior to that of the individual compounds. Overall, the most significant differences in activity between combined and isolated treatments were observed for MurD in <i>S. aureus</i> and SidA in <i>K. pneumoniae</i>. These findings suggest that SMs may serve as potential candidates for the development of synergistic or additive molecules to be used alongside conventional antibiotics, representing a promising strategy to mitigate AMR and offer viable and effective therapeutic alternatives.</p>

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Screening of Secondary Metabolites with Synergistic Potential Associated with Amoxicillin: An In Vitro and In Silico Approach

  • 期刊论文

  • 发表日期：

    2025年11月8日

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  • Amanda Vieira de Barros,
  • Gabriela de Lima Menezes,
  • Bruno Oliveira de Veras,
  • Patryck Érmerson Monteiro dos Santos,
  • Umberto Laino Fulco,
  • Patrícia Maria Guedes Paiva,
  • Márcia Vanusa da Silva,
  • Guilherme Fernandes Teixeira,
  • Ivo Cavalcante Pita Neto,
  • Henrique Douglas Melo Coutinho,
  • Maria Betânia Melo de Oliveira

摘要

The advancement of Antimicrobial Resistance (AMR) and the lack of effective treatments demand the development of new drugs to combat resistant bacteria. Plants, in turn, produce various Secondary Metabolites (SMs) with diverse molecular structures, which are promising therapeutic alternatives. This study aims to evaluate the potential of 13 plant derived SMs in modulating bacterial resistance to amoxicillin (AMO), and to investigate the mechanisms of action against Staphylococcus aureus (ATCC 29213) and Klebsiella pneumoniae (UFPDA 396) using Molecular Docking (MD) simulations. Among the tested SMs, p-Cymene (CYM) showed the best activity against S. aureus, with a Minimum Inhibitory Concentration (MIC) of 512 µg/mL, while Eugenol (EUG) was most effective against K. pneumoniae, with an MIC of 1024 µg/mL. In resistance modulation assays using the checkerboard method, SMs including EUG, CYM, α-pinene (APN), β-pinene (BPN), Geraniol (GER), Linalool (LNL), and Myrcene (MYR) exhibited synergistic effects when combined with AMO, with Fractional Inhibitory Concentration Index (FICI) values ranging from 0.1 to 0.5. Additionally, both the SMs and AMO, as well as their synergistic combinations, were docked to molecular targets associated with resistance and virulence in S. aureus and K. pneumoniae. The drug–protein complexes showed favorable interaction energies, confirming that the binding free energy of the synergistic combinations was superior to that of the individual compounds. Overall, the most significant differences in activity between combined and isolated treatments were observed for MurD in S. aureus and SidA in K. pneumoniae. These findings suggest that SMs may serve as potential candidates for the development of synergistic or additive molecules to be used alongside conventional antibiotics, representing a promising strategy to mitigate AMR and offer viable and effective therapeutic alternatives.