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The licorice pentacyclic triterpenoid component 18β-glycyrrhetinic acid enhances the activity of antibiotics against strains of methicillin-resistant Staphylococcus aureus

Abstract

This study aimed to identify compounds that enhance the activity of current antibiotics against multidrug-resistant bacteria. Screening of a 350+ compound proprietary small molecules library revealed that the Glycyrrhiza glabra (licorice)-derived triterpenoid 18β-glycyrrhetinic acid (18β-GA) potentiated the antibacterial activity of certain antibiotics against Staphylococcus aureus. Here, we evaluated the ability of pentacyclic triterpenoids to potentiate the activity of antibiotics against strains of methicillin-resistant S. aureus (MRSA). Checkerboard assays were used to assess the minimum inhibitory concentration (MIC) of tobramycin and ten pentacyclic triterpenoids against S. aureus. The effect of 18β-GA on the MIC of different antibiotics against MRSA was also determined in an in vitro airway MRSA infection model. 18β-GA enhanced the bactericidal activity of the aminoglycosides tobramycin, gentamicin and amikacin, and of polymyxin B against two MRSA strains, reducing the MIC of these antibiotics 32–64-fold [fractional inhibitory concentration index (FICI) of 0.12–0.13]. Other β-amyrin triterpenoids and α-amyrin triterpenoids did not exert such synergistic effects. 18β-GA did not enhance the activity of antibiotics from other structural classes against the MRSA strains. In an air-exposed airway epithelial cell culture, 18β-GA enhanced the bactericidal activity of tobramycin and polymyxin B against the MRSA strain. These data demonstrate the potential of 18β-GA to synergise with certain types of antibiotics to eliminate strains of MRSA.

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Acknowledgements

The authors wish to thank E. Erdem, S. Kruithof and M. van den Hoven for their help with the assays.

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Correspondence to P. C. de Visser.

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Funding

This research was funded, in part, by the Dutch Top Institute Pharma under project T4-211.

Conflict of interest

TK and PdV are employed by BioMarin Nederland BV.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors. Bronchial tissues for human bronchial epithelial cell models are present in a biobank at the LUMC and contains cells from anonymised tumour-free tissue, obtained from patients who underwent a lobectomy or pneumectomy for lung cancer, as previously described (van Wetering et al., J Investig Med 48(5):359–366, 2000). The design and procedures used for the biobank were approved by the local medical ethical committee.

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de Breij, A., Karnaoukh, T.G., Schrumpf, J. et al. The licorice pentacyclic triterpenoid component 18β-glycyrrhetinic acid enhances the activity of antibiotics against strains of methicillin-resistant Staphylococcus aureus . Eur J Clin Microbiol Infect Dis 35, 555–562 (2016). https://doi.org/10.1007/s10096-015-2570-z

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  • DOI: https://doi.org/10.1007/s10096-015-2570-z

Keywords

  • Minimum Inhibitory Concentration
  • Tobramycin
  • Minimum Bactericidal Concentration
  • Betulinic Acid
  • Human Bronchial Epithelial Cell