Phytomedicine 15 (2008) 1125–1129 SHORT COMMUNICATION Inhibiting enoyl-ACP reductase (FabI) across pathogenic microorganisms by linear sesquiterpene lactones from Anthemis auriculata Anastasia Karioti a , Helen Skaltsa a , Xujie Zhang b , Peter J. Tonge b , Remo Perozzo c , Marcel Kaiser d , Scott G. Franzblau e , Deniz Tasdemir f,Ã a Department of Pharmacognosy and Chemistry of Natural Products, School of Pharmacy, University of Athens, 157 71 Athens, Greece b Institute for Chemical Biology and Drug Discovery, Department of Chemistry, Stony Brook University, NY 11794-3400, USA c School of Pharmaceutical Sciences, University of Geneva, 1211 Geneva 4, Switzerland d Department of Medical Parasitology, Swiss Tropical Institute, 4002 Basel, Switzerland e Institute for Tuberculosis Research, College of Pharmacy, University of Illinois at Chicago, Chicago, IL 60612, USA f Centre for Pharmacognosy and Phytotherapy, School of Pharmacy, University of London, London WC1N 1AX, UK 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, b-ketoacyl-ACP reductase (PfFabG) and b-hydroxyacyl-ACP deydratase (PfFabZ). The compounds showed clear differentiation in inhibition of FabI enzymes from different microorganisms. Anthecotulide (1) was most active against MtFabI (IC 50 4.5 mg/ml), whereas the oxygenated derivatives thereof (compounds 2 and 3) specifically inhibited plasmodial FAS-II enzymes, PfFabI and PfFabG (IC 50 values 20–75 mg/ml). All compounds were inactive towards EcFabI. In whole cell assays, all three compounds exhibited antimalarial and antibacterial activities. r 2008 Elsevier GmbH. All rights reserved. Keywords: Sesquiterpene lactone; Anthecotulide; Anthemis auriculata; Plasmodium falciparum; Mycobacterium tuberculosis; Escherichia coli; Fatty acid biosynthesis; FabI Introduction Fatty acid (FA) biosynthesis is a metabolic pathway by which acetyl-CoA is converted into short to long chain FAs. In plants, bacteria and some Apicomlexan parasites such as Plasmodium falciparum, it is carried out by the type II fatty acid synthase (FAS-II), a multienzyme complex that differs totally from the multifunctional human FAS-I (Smith et al., 2003). FA biosynthesis includes seven enzymatic steps, three of which are involved in the initiation phase and four in the elongation cycle. The formation of FAs is vital to survival, therefore the inhibition of individual enzymes of the pathway (e.g. FabG, FabZ; FabI and FabB/F) is an established approach in antimicrobial drug discovery (Heath et al., 2002; Zhang et al., 2006; Goodman and ARTICLE IN PRESS www.elsevier.de/phymed 0944-7113/$ - see front matter r 2008 Elsevier GmbH. All rights reserved. doi:10.1016/j.phymed.2008.02.018 Ã Corresponding author. Tel.: +44 20 7753 5845; fax: +44 20 7753 5909. E-mail address: deniz.tasdemir@pharmacy.ac.uk (D. Tasdemir).