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Restoration of antibacterial activity of β‐lactams by epigallocatechin gallate against β‐lactamase‐producing species depending on location of β‐lactamase

The combined effects of (–)‐epigallocatechin gallate (EGCg) and β‐lactams were investigated against various β‐lactamase‐producing clinical isolates, including 21 Staphylococcus aureus, 6 Escherichia coli, 3 Klebsiella pneumoniae and 8 Serratia marcescens strains. Penicillin in combination with EGCg at 12.5μg mL−1 showed the most potent synergy against 100% penicillinase‐producing S. aureus. However, cefotaxime or imipenem in combination with higher concentration of EGCg (100 μg mL−1) only showed slight synergy against 2 of 17 Gram‐negative rods. Similar to the effect on the penicillinase from S. aureus, however, EGCg also directly inhibited the extracted β‐lactamases from the Gram‐negative rods, thereby protecting β‐lactams from inactivation. The different effects of the combinations on different β‐lactamase‐producing species were confirmed to be related to the cellular locations of β‐lactamases. In contrast to a 32.7% extracellular fraction of total β‐lactamase activity in a penicillinase‐producing S. aureus, the fractions were 0.6%, 0.6% and 1.2% in a TEM‐derived extended‐spectrum β‐lactamase‐producing E. coli, an inhibitor‐resistant β‐lactamase‐producing K. pneumoniae and an IMP‐producing S. marcescens, respectively. In conclusion, the combination of penicillin with EGCg showed potent synergy against penicillinase‐producing S. aureus in‐vitro. The combinations of β‐lactams and EGCg against β‐lactamase‐producing Gram‐negative rods do indicate a limitation owing to the cellular location of β‐lactamases.