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Papers In Press, published online ahead of print May 7, 2004
Infectious Diseases, St. Jude Childrens Research Hospital, Memphis, TN 38105-2794
Corresponding Author: charles.rock{at}stjude.org
Epigallocatechin gallate (EGCG) is the major component of green tea extracts and possesses antibacterial, antiviral and antitumor activity. Our study focused on validating the inhibition of the bacterial type II fatty acid synthesis system as a mechanism for the antibacterial effects of EGCG and related plant polyphenols. EGCG, and the related tea catechins, potently inhibited both the FabG and FabI reductase steps in the fatty acid elongation cycle with IC50s between 5 and 15 M. The presence of the galloyl moiety was essential for activity, and EGCG was a competitive inhibitor of FabI and a mixed-type inhibitor of FabG demonstrating that EGCG interfered with cofactor binding in both enzymes. EGCG inhibited acetate incorporation into fatty acids in vivo, although it was much less potent than thiolactomycin, a validated fatty acid synthesis inhibitor, and overexpression of FabG, FabI or both did not confer resistance. A panel of other plant polyphenols was screened for FabG/FabI inhibition and antibacterial activity. Most of these inhibited both reductase steps, possessed antibacterial activity, and inhibited cellular fatty acid synthesis. The ability of the plant secondary metabolites to interfere with the activity of multiple NAD(P)-dependent cellular processes must be taken into account when assessing the specificity of their effects.
J. Biol. Chem, 10.1074/jbc.M403697200
Submitted on April 2, 2004
Revised on May 7, 2004
Accepted on May 7, 2004
Evaluation of epigallocatechin gallate and related plant polyphenols as Inhibitors of the FabG and FabI reductases of bacterial type II fatty acid synthase
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