title: 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.
authors.affiliation: Department of Infectious Diseases, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands.
authors.forename: A
authors.initials: A
authors.lastname: de Breij
authors.affiliation: BioMarin Nederland BV, J.H. Oortweg 21, 2333 CH, Leiden, The Netherlands.
authors.forename: T G
authors.initials: TG
authors.lastname: Karnaoukh
authors.affiliation: Department of Pulmonology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands.
authors.forename: J
authors.initials: J
authors.lastname: Schrumpf
authors.affiliation: Department of Pulmonology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands.
authors.forename: P S
authors.initials: PS
authors.lastname: Hiemstra
authors.affiliation: Department of Infectious Diseases, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands.
authors.forename: P H
authors.initials: PH
authors.lastname: Nibbering
authors.affiliation: Department of Infectious Diseases, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands.
authors.forename: J T
authors.initials: JT
authors.lastname: van Dissel
authors.affiliation: BioMarin Nederland BV, J.H. Oortweg 21, 2333 CH, Leiden, The Netherlands. peter.devisser@bmrn.com.
authors.forename: P C
authors.initials: PC
authors.lastname: de Visser
mesh_terms: D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics*; D002460:Cell Line; D004357:Drug Synergism; D004847:Epithelial Cells / Q000382:microbiology; D006034:Glycyrrhetinic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects*; D008826:Microbial Sensitivity Tests; D050296:Microbial Viability / Q000187:drug effects; D008954:Models, Biological
chemical_list: D000900:Anti-Bacterial Agents; C119129:18alpha-glycyrrhetinic acid; D006034:Glycyrrhetinic Acid