Synergistic interactions between phenolic compounds identified in grape pomace extract with antibiotics of different classes against Staphylococcus aureus and Escherichia coli

PLoS One. 2017 Feb 24;12(2):e0172273. doi: 10.1371/journal.pone.0172273. eCollection 2017.


Synergy could be an effective strategy to potentiate and recover antibiotics nowadays useless in clinical treatments against multi-resistant bacteria. In this study, synergic interactions between antibiotics and grape pomace extract that contains high concentration of phenolic compounds were evaluated by the checkerboard method in clinical isolates of Staphylococcus aureus and Escherichia coli. To define which component of the extract is responsible for the synergic effect, phenolic compounds were identified by RP-HPLC and their relative abundance was determined. Combinations of extract with pure compounds identified there in were also evaluated. Results showed that the grape pomace extract combined with representatives of different classes of antibiotics as β-lactam, quinolone, fluoroquinolone, tetracycline and amphenicol act in synergy in all S. aureus and E. coli strains tested with FICI values varying from 0.031 to 0.155. The minimal inhibitory concentration (MIC) was reduced 4 to 75 times. The most abundant phenolic compounds identified in the extract were quercetin, gallic acid, protocatechuic acid and luteolin with relative abundance of 26.3, 24.4, 16.7 and 11.4%, respectively. All combinations of the extract with the components also showed synergy with FICI values varying from 0.031 to 0.5 and MIC reductions of 4 to 125 times with both bacteria strains. The relative abundance of phenolic compounds has no correlation with the obtained synergic effect, suggesting that the mechanism by which the synergic effect occurs is by a multi-objective action. It was also shown that combinations of grape pomace extract with antibiotics are not toxic for the HeLa cell line at concentrations in which the synergistic effect was observed (47 μg/mL of extract and 0.6-375 μg/mL antibiotics). Therefore, these combinations are good candidates for testing in animal models in order to enhance the effect of antibiotics of different classes and thus restore the currently unused clinical antibiotics due to the phenomenon of resistance. Moreover, the use of grape pomace is a good and low-cost alternative for this purpose being a waste residue of the wine industry.

MeSH terms

  • Animals
  • Anti-Bacterial Agents / pharmacology
  • Chloramphenicol / pharmacology
  • Chromatography, High Pressure Liquid
  • Drug Resistance, Microbial / drug effects
  • Drug Synergism*
  • Escherichia coli / drug effects
  • Escherichia coli / pathogenicity
  • Escherichia coli Infections / drug therapy*
  • Escherichia coli Infections / microbiology
  • HeLa Cells
  • Humans
  • Methicillin-Resistant Staphylococcus aureus / drug effects
  • Methicillin-Resistant Staphylococcus aureus / pathogenicity
  • Phenols / chemistry
  • Phenols / pharmacology*
  • Plant Extracts / chemistry
  • Plant Extracts / pharmacology*
  • Staphylococcal Infections / drug therapy*
  • Staphylococcal Infections / microbiology
  • Tetracyclines / pharmacology
  • Vitis / chemistry


  • Anti-Bacterial Agents
  • Phenols
  • Plant Extracts
  • Tetracyclines
  • Chloramphenicol

Grants and funding

This study was supported financially under Fondo Nacional de Desarrollo Científico y Tecnológico (FONDECYT) project 1130389 and by the Dirección de Investigación en Ciencia y Tecnología (DICYT-USACH). L. Sanhueza thanks the Comisión Nacional de Ciencia y Tecnología (CONICYT) for its support of her doctoral studies. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.