Inhibiting enoyl-ACP reductase (FabI) across pathogenic microorganisms by linear sesquiterpene lactones from Anthemis auriculata

Karioti, Anastasia; Skaltsa, Helen; Zhang, Xujie; Tonge, Peter J.; Perozzo, Remo; Kaiser, Marcel; Franzblau, Scott G.; Tasdemir, Deniz

doi:10.1016/j.phymed.2008.02.018

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Volume 15, Issue 12 , Pages 1125-1129, December 2008

Inhibiting enoyl-ACP reductase (FabI) across pathogenic microorganisms by linear sesquiterpene lactones from Anthemis auriculata

Anastasia Karioti
- Department of Pharmacognosy and Chemistry of Natural Products, School of Pharmacy, University of Athens, 157 71 Athens, Greece
Helen Skaltsa
- Department of Pharmacognosy and Chemistry of Natural Products, School of Pharmacy, University of Athens, 157 71 Athens, Greece
Xujie Zhang
- Institute for Chemical Biology and Drug Discovery, Department of Chemistry, Stony Brook University, NY 11794-3400, USA
Peter J. Tonge
- Institute for Chemical Biology and Drug Discovery, Department of Chemistry, Stony Brook University, NY 11794-3400, USA
Remo Perozzo
- School of Pharmaceutical Sciences, University of Geneva, 1211 Geneva 4, Switzerland
Marcel Kaiser
- Department of Medical Parasitology, Swiss Tropical Institute, 4002 Basel, Switzerland
Scott G. Franzblau
- Institute for Tuberculosis Research, College of Pharmacy, University of Illinois at Chicago, Chicago, IL 60612, USA
Deniz Tasdemir
- Centre for Pharmacognosy and Phytotherapy, School of Pharmacy, University of London, London WC1N 1AX, UK
- Corresponding author. Tel.: +442077535845; fax: +442077535909.

Abstract

Enoyl-ACP reductase (FabI) is a key enzyme of the type II fatty acid biosynthesis (FAS-II) pathway and a validated antimicrobial target. In the current study, three linear sesquiterpene lactones obtained from Anthemis auriculata, namely anthecotulide (1), 4-hydroxyanthecotulide (2) and 4-acetoxyanthecotulide (3) were evaluated for specific inhibitory effects against the FabI enzyme from three pathogenic microorganisms, Plasmodium falciparum (PfFabI), Mycobacterium tuberculosis (MtFabI) and Escherichia coli (EcFabI). In addition, the compounds were also tested against two elongation enzymes from the plasmodial FAS-II system, β-ketoacyl-ACP reductase (PfFabG) and β-hydroxyacyl-ACP deydratase (PfFabZ). The compounds showed clear differentiation in inhibition of FabI enzymes from different microorganisms. Anthecotulide (1) was most active against MtFabI (IC₅₀ 4.5μg/ml), whereas the oxygenated derivatives thereof (compounds 2 and 3) specifically inhibited plasmodial FAS-II enzymes, PfFabI and PfFabG (IC₅₀ values 20–75μg/ml). All compounds were inactive towards EcFabI. In whole cell assays, all three compounds exhibited antimalarial and antibacterial activities.