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Antimicrobial Agents and Chemotherapy, June 2001, p. 1737-1742, Vol. 45, No. 6
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.6.1737-1742.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Mechanism of Synergy between Epigallocatechin Gallate and beta -Lactams against Methicillin-Resistant Staphylococcus aureus

Wei-Hua Zhao,1,* Zhi-Qing Hu,1 Sachie Okubo,1 Yukihiko Hara,2 and Tadakatsu Shimamura1

Department of Microbiology and Immunology, Showa University School of Medicine,1 and Tokyo Food Techno Co., Ltd.,2 Tokyo, Japan

Received 11 September 2000/Returned for modification 15 January 2001/Accepted 21 March 2001

Compared to MICs (more than 800 µg/ml) of (-)-epigallocatechin gallate (EGCg) against Escherchia coli, MICs of EGCg against methicillin-susceptible and methicillin-resistant Staphylococcus aureus (MSSA and MRSA) were 100 µg/ml or less. Furthermore, less than 25 µg EGCg per ml obviously reversed the high level resistance of MRSA to all types of tested beta -lactams, including benzylpenicillin, oxacillin, methicillin, ampicillin, and cephalexin. EGCg also induced a supersusceptibility to beta -lactams in MSSA which does not express mecA, encoding penicillin-binding protein 2' (PBP2'). The fractional inhibitory concentration (FIC) indices of the tested beta -lactams against 25 isolates of MRSA were from 0.126 to 0.625 in combination with 6.25, 12.5 or 25 µg of EGCg per ml. However, no synergism was observed between EGCg and ampicillin against E. coli. EGCg largely reduced the tolerance of MRSA and MSSA to high ionic strength and low osmotic pressure in their external atmosphere, indicating damage of the cell wall. Unlike dextran and lipopolysaccharide, peptidoglycan from S. aureus blocked both the antibacterial activity of EGCg and the synergism between EGCg and oxacillin, suggesting a direct binding of EGCg with peptidoglycan on the cell wall. EGCg showed a synergistic effect with DL-cycloserine (an inhibitor of cell wall synthesis unrelated to PBP2') but additive or indifferent effect with inhibitors of protein and nuclear acid synthesis. EGCg did not suppress either PBP2' mRNA expression or PBP2' production, as confirmed by reverse transcription-PCR and a semiquantitative PBP2' latex agglutination assay, indicating an irrelevance between the synergy and PBP2' production. In summary, both EGCg and beta -lactams directly or indirectly attack the same site, peptidoglycan on the cell wall. EGCg synergizes the activity of beta -lactams against MRSA owing to interference with the integrity of the cell wall through direct binding to peptidoglycan.

* Corresponding author. Mailing address: Department of Microbiology and Immunology, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan. Phone: 81-3-3784-8131. Fax: 81-3-3784-3069. E-mail: whzhao{at}med.showa-u.ac.jp.

Antimicrobial Agents and Chemotherapy, June 2001, p. 1737-1742, Vol. 45, No. 6
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.6.1737-1742.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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