Green Tea Catechins Potentiate Triclosan Binding to Enoyl-ACP Reductase from Plasmodium falciparum (PfENR)

Abstract

We have investigated the mechanism of inhibition of enoyl-acyl carrier protein reductase of Plasmodium falciparum (PfENR) by triclosan in the presence of a few important catechins and related plant polyphenols. The examined flavonoids inhibited PfENR reversibly with Ki values in the nanomolar range, EGCG being the best with 79 +/- 2.67 nM. The steady-state kinetics revealed time dependent inhibition of PfENR by triclosan, demonstrating that triclosan exhibited slow tight-binding kinetics with PfENR in the presence of these compounds. Additionally, all of them potentiated the binding of triclosan with PfENR by a two-step mechanism resulting in an overall inhibition constant of triclosan in the low picomolar concentration range. The high affinities of tea catechins and the potentiation of binding of triclosan in their presence are readily explained by molecular modeling studies. The enhancement in the potency of triclosan induced by these compounds holds great promise for the development of effective antimalarial therapy.

Flavonoid inhibitors as novel antimycobacterial agents targeting Rv0636, a putative dehydratase enzyme involved in Mycobacterium tuberculosis fatty acid synthase II

“…A high level of resistance was not observed, indicating that the flavonoids might target several FAS-II enzymes. This was not surprising since flavonoids inhibit several FAS-II enzymes as shown in inhibition studies using E. coli and P. falciparum (Sharma et al, 2007;Tasdemir et al, 2006;Zhang & Rock, 2004) (Table 1). The overexpression of Rv0636 also had little or no effect on both 2,29,49-trihydroxychalcone and fisetin activity in vivo against M. bovis BCG (Table 3).…”

“…Previously, flavonoid compounds have been shown to be active against E. coli and P. falciparum in vivo and have been shown to inhibit FAS-II components (Sharma et al, 2007;Tasdemir et al, 2006;Zhang & Rock, 2004). Five flavonoids were evaluated for their potential as myco- bacterial FAS-II inhibitors in vivo.…”

“…Here, for FAS-II reactions, 0.1 mg protein, 10 mM palmitoyl-CoA and 45 nCi [ 2006; Zhang & Rock, 2004). Butein, a product of Rhus verniciflua, quercetin from Flaveria bidentis and fisetin from Rhus cotinus target the enoyl-ACP reductases of both P. falciparum and E. coli at relatively low concentrations (Sharma et al, 2007;Tasdemir et al, 2006;Zhang & Rock, 2004). Isoliquirtigenin and 2,29,49-trihydroxychalcone, related products of Dalbergia odorifera inhibit both the enoyl-ACP and b-ketoacyl-ACP reductases of E. coli (Zhang & Rock, 2004).…”

X-ray Structural Analysis of Plasmodium falciparum Enoyl Acyl Carrier Protein Reductase as a Pathway toward the Optimization of Triclosan Antimalarial Efficacy

“…Building on initial investigations into plant polyphenols as antibacterial FAS-II inhibitors (59), other researchers have independently examined natural product inhibitors of PfENR where a common structural theme is the presence of one or more phenolic moieties (60,61). Interestingly, select members of the green tea catechin family were high nanomolar inhibitors of PfENR alone while also potentiating the efficacy of triclosan inhibition proposedly through the formation of a PfENR⅐catechin⅐triclosan complex (62).…”

Design, development, synthesis, and docking analysis of 2′‐substituted triclosan analogs as inhibitors for Plasmodium falciparum Enoyl‐ACP reductase

“…We have reported earlier that triclosan, a microbicide and a common additive in many household items, strongly inhibits PfENR with high potency and also exhibits slow-tight binding mechanism in presence of catechins (16,17). Exploiting structure-function relationship, we have also developed a number of triclosan derivatives as inhibitors of PfENR many of which showed inhibition constants in low-nanomolar range.…”