title: Inhibiting enoyl-ACP reductase (FabI) across pathogenic microorganisms by linear sesquiterpene lactones from Anthemis auriculata.
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, beta-ketoacyl-ACP reductase (PfFabG) and beta-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 microg/ml), whereas the oxygenated derivatives thereof (compounds 2 and 3) specifically inhibited plasmodial FAS-II enzymes, PfFabI and PfFabG (IC(50) values 20-75 microg/ml). All compounds were inactive towards EcFabI. In whole cell assays, all three compounds exhibited antimalarial and antibacterial activities.
authors.affiliation: Department of Pharmacognosy and Chemistry of Natural Products, School of Pharmacy, University of Athens, 157 71 Athens, Greece.
authors.forename: Anastasia
authors.initials: A
authors.lastname: Karioti
authors.forename: Helen
authors.initials: H
authors.lastname: Skaltsa
authors.forename: Xujie
authors.initials: X
authors.lastname: Zhang
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Tonge
authors.forename: Remo
authors.initials: R
authors.lastname: Perozzo
authors.forename: Marcel
authors.initials: M
authors.lastname: Kaiser
authors.forename: Scott G
authors.initials: SG
authors.lastname: Franzblau
authors.forename: Deniz
authors.initials: D
authors.lastname: Tasdemir
mesh_terms: D000818:Animals; D031166:Anthemis / Q000737:chemistry*; D000900:Anti-Bacterial Agents / Q000302:isolation & purification / Q000494:pharmacology; D000962:Antimalarials / Q000302:isolation & purification / Q000494:pharmacology; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors; D050753:Enoyl-(Acyl-Carrier-Protein) Reductase (NADH) / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000302:isolation & purification / Q000494:pharmacology; D004926:Escherichia coli / Q000201:enzymology; D007783:Lactones / Q000302:isolation & purification / Q000494:pharmacology*; D009169:Mycobacterium tuberculosis / Q000201:enzymology; D010963:Plasmodium falciparum / Q000201:enzymology; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors; D012717:Sesquiterpenes / Q000302:isolation & purification / Q000494:pharmacology*
chemical_list: C510712:4-O-acetoxyanthecotulide; C510711:4-hydroxyanthecotulide; D000900:Anti-Bacterial Agents; D000962:Antimalarials; D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D007783:Lactones; D015800:Protozoan Proteins; D012717:Sesquiterpenes; C499300:anthecotulide; D050753:Enoyl-(Acyl-Carrier-Protein) Reductase (NADH)