Evaluation of Epigallocatechin Gallate and Related Plant Polyphenols as Inhibitors of the FabG and FabI Reductases of Bacterial Type II Fatty-acid Synthase

Abstract

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 IC 50 values 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.

Inhibitory activity of chlorogenic acid on enzymes involved in the fatty acid synthesis in animals and bacteria

“…Although chlorogenic acid has been reported to have anticancer and antibacterial effects (24,25), little is known about the molecular mechanisms through which chlorogenic acid inhibits carcinogenesis and the growth of bacteria. Based on the current results, these effects afforded by chlorogenic acid probably was, as least partially, related to the inhibition of FAS I in cancer cells and of those enzymes involved in the bacterial fatty acid synthesis, such as FabI (31) and FabG, because the inhibition of fatty acid synthesis could lead to the suppression of the growth of cancer cells and bacteria (9,35). Although chlorogenic acid did not show very potently inhibitory activity against fowl FAS and FabG from Escherichia coli, considering that the susceptibilities of fatty acid synthases of various sources to chlorogenic acid were different, chlorogenic acid, a plant secondary metabolic and common in human foods, still exhibited clinical or preventive potential in the treatment of some relative human diseases.…”

“…6), some similarities were observed. Chlorogenic acid could resemble the phenyl ring and galloyl moiety of EGCG, the effective portion as a FAS inhibitor (35), and both inhibitors are possibly similar to some part of NADPH, maybe the two ribose groups. All of them are rich in hydroxyl groups and oxygen atoms, and could bind to the acceptor by forming hydrogen bonds.…”

“…It was possibly caused by the improper position of the ester bond in the chlorogenic acid. Recently, EGCG and analogues were regarded as novel leading compounds of FAS inhibitors (14,15,35), therefore chlorogenic acid, as a mechanical analogue of EGCG, could offer some structural information for the future development of specific potent inhibitors of fatty acid synthesis in bacterial and human systems. Although chlorogenic acid has been reported to have anticancer and antibacterial effects (24,25), little is known about the molecular mechanisms through which chlorogenic acid inhibits carcinogenesis and the growth of bacteria.…”

Macrolactin S, a New Antibacterial Agent with Fab G-inhibitory Activity from Bacillus sp. AT28

“…Since the FabG gene is well conserved in most pathogenic bacteria, it is considered to be a new potential target for broad-spectrum antibacterial agents. Epigallocatechin gallate and related polyphenol compounds have been reported to inhibit E. coli FabG [4]. Some inhibitors of other bacterial FAS are known.…”

Atromentin and Leucomelone, the First Inhibitors Specific to Enoyl-ACP Reductase (FabK) of Streptococcus pneumoniae

“…For example, phenolic compounds such as rhein, gossypol, or resveratrol have been reported to be extruded by a multidrug resistance (MDR) pump in P. aeruginosa, E. coli, or Salmonella enterica, since their antibacterial activity was uncovered by the treatment with MDR inhibitors, MC 207110 or INF 271 , or in an MDR mutant. Also, some cathechin gallates or flavanone-3-ols such as fustin and taxifolin were reported not to exhibit antibacterial activity against E. coli while other flavonols such as fisetin and quercetin showed antibacterial activity, although all of them inhibited E. coli FabI [11]. AG205, a potent FabK-inhibitory, has been reported to show reduced activity against some S. pneumoniae isolates, which was assumed to be due to an efflux pump [17].…”