The Combination of Catechin and Epicatechin Gallate from Fructus Crataegi Potentiates β-Lactam Antibiotics Against Methicillin-Resistant Staphylococcus aureus (MRSA) in Vitro and in Vivo

Fructus crataegi (hawthorn) is the common name of all plant species in the genusCrataegusof the Rosaceae family. In the present study, three monomers of (+)-catechin (C), (−)-epicatechin gallate (ECg) and (−)-epigallocatechin (EGC) were isolated from the hawthorn under the guide of antibacterial sensitization activity. The bioactivity of the composite fraction in enhancing the antibacterial effect of oxacillin against methicillin-resistantStaphylococcus aureus(MRSA) was greater than that of the individual monomer of the hawthorn extractin vitro. Two-fold dilution and checkerboard methods were used to analyze antibacterial activity and screen for the combination and proportion of monomers with the best bioactivity. The result showed that C (128 mg/L) combined with ECg (16 mg/L) had the greatest effect and the combination also reduced the bacterial load in blood of septic mice challenged with a sublethal dose of MRSA, increased daunomycin accumulation within MRSA and down-regulated the mRNA expression ofnorA,norCandabcA, three important efflux pumps of MRSA. In summary, C and ECg enhanced the antibacterial effect of β-lactam antibiotics against MRSAin vitroandin vivo, which might be related to the increased accumulation of antibiotics within MRSA via suppression of important efflux pumps’ gene expression.Keywords:fructus crataegi;(+)-catechin;(−)-epicatechin gallate;synergistic effect;MRSA;drug accumulation