Abstract
Fructus crataegi (hawthorn) is the common name of all plant species in the genus Crataegus of 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-resistant Staphylococcus aureus (MRSA) was greater than that of the individual monomer of the hawthorn extract in 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 of norA, norC and abcA, three important efflux pumps of MRSA. In summary, C and ECg enhanced the antibacterial effect of β-lactam antibiotics against MRSA in vitro and in vivo, which might be related to the increased accumulation of antibiotics within MRSA via suppression of important efflux pumps’ gene expression.
Highlights
Methicillin-Resistant Staphylococcus aureus (MRSA) is the major multi-resistant pathogen causing serious healthcare-associated and community-onset infection, which carry high morbidity and mortality [1]
The main resistance mechanisms of methicillin-resistant Staphylococcus aureus (MRSA) to the β-lactam antibiotics are a large expression of β-lactamase to destroy β-lactams by hydrolysis, an acquisition of the mecA gene to encode the penicillin-binding protein 2a (PBP2a) with low affinity to β-lactam antibiotics [3], and an expression of efflux pumps to extrude antibiotics or other toxic agents from the pathogen [4]
The combination of C and epicatechin gallate (ECg) (Table 1) or of C, ECg and EGC showed strong ILSMR effects, with Fractional inhibitory concentration index (FICI) lower than 0.5 (Table 2), and there was no significant difference between two combinations
Summary
Methicillin-Resistant Staphylococcus aureus (MRSA) is the major multi-resistant pathogen causing serious healthcare-associated and community-onset infection, which carry high morbidity and mortality [1]. More than efflux pumps have been discovered for S. aureus [5] These pumps show different substrate specificity, most of them are capable of extruding compounds of different kinds of antibiotics, providing the pathogen the means to develop a multidrug resistance phenotype. Researching new agents is very difficult, and the propensity to increase resistant strains will occur when the agent applied is extensively used in clinic Another approach is to develop new agents that can enhance the effect of existing antimicrobial drugs—these are called antibacterial drug sensitizers—via modifying the bacterial phenotype to sensitize MRSA to previously ineffective antibiotics rather than the direct killing of bacteria. Catechin can intensify the susceptibility of MRSA to β-lactam antibiotics despite themselves having very weak or no antimicrobial effects against MRSA [16].
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