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


Enoyl-ACP reductase (FabI) is a key enzyme of the type II fatty acid biosynthesis (FAS-II) pathway and validated antimicrobial target. In the current study, three linear sesquiterpene lactones obtained from Anthemis auriculata. namely antheocotulide (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 inhibiton of FabI enzymes from different microorganisms. Anthecotulide (1) was most active against MtFabI (I[C.sub.50] 4.5 [micro]g/ml), whereas the oxygenated derivatives thereof (compounds 2 and 3) specifically inhibited plasmodial FAS-II enzymes, PfFabI and PfFabG (I[C.sub.50] values 20-75 [micro]g/ml). All compounds were inactive towards EcFabI. In whole cell assays, all three compounds exhibited antimalarial and antibacterial activities.

[c] 2008 Elsevier GmbH. All rights reserved.

Keywords: Sesquiterpene lactone; Anthecotulide; Anthemis auriculata; Plasmodium; Mycobacterium tuberculosis; Escherichia coli; Fatty acid biosynthesis; FabI


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-II (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 (Health et al., 2002; Zhang et al., 2006; Goodman and McFadden, 2007). Bacterial FAS-II pathwayis located in the cytoplasm, whereas in P. falciparum the FAS-II system (PfFAS-II) takes place in the apicoplast, a previously discovered chloroplast-like organelle (McFadden et al., 1996), which is thought to have arisen from an ancient cyanobacterial endosymbiont through the process of secondary endosymbiosis (Williams and Keeling, 2003). Because of its cyanobacterial origin, there are significant similarities in the organization and overall structures of the bacterial and plasmodial FAS-II enzymes (Muench et al., 2007). Consistent with this, the inhibitors often exhibit cross activity towards FAS-II enzymes of different origin. For example, triclosan, a very potent inhibitor of Escherichia coli FabI enzyme (EcFAbI) (Sivaraman et al., 2003) also inhibits PfFabI with a similar potency and mechanism (Surolia and Surolia, 2001; Kapoor et al., 2004). WE have been engaged for some time in the discovery of natural products targeting PfFAS-II enzymes (Tasdemir et al., 2005, 2006; Karioti et al., 2007), particularly PfFabI, a crucial enzyme catalyzing the final reductin of the FA intermediates in each elongation cycle. In order to establish species selectivity, we have recently started testing our natural PfFabI inhibitors toward FabI homologous of various pathogenic organisms. We recently reported the first marine natural products inhibiting FabI of P. falciparum (PfFabI), the causative agent of human malaria, Mycobacterium tuberculosis (MtFabI), the causative agent of pulmonary tuberculosis and E. Coli (EcFabI), the causative agent of gastroenteritis, neonatal meningitis and urinary tract infections (Tasdemir et al., 2007).

The genus Anthemis (Asteraceae) comprises about 130 species predominately distributed around the Mediterranean area, several of which are used as aromatic and herbal medicines, insecticides and dyes (Fernandes, 1976; Mabberley, 1997). Anthemis auriculata Boiss. is an endemic plant of the South Balkan Peninsula and Turnkey (Fernandes, 1976). In a recent communication, we reported three linear sesquiterpene lactones (SLs) anthecotulide (1), 4-hydroxyanthecotulide (2) and 4-acetoxyanthecotulide (3) with antibacterial activity from Greek A. auriculata (Theodori et al., 2006). We also described the isolation and structure elucidation of anthecularin (4), a minor, cyclic SL with a novel ring system from the same plant that exhibited dual PfFAS-II enzyme inhibitory activity (Karioti et al., 2007). This bioactivity encouraged us to test the related irregular SLs 1-3 against PfFabI, as well as MtFabI and EcFabI. In addition, the compounds were screened toward two toehr recombinant enzymes, [beta]-ketoacyl-ACP reductase (PfFabG) and [beta]-hydroxyacyl-ACP deydratase (PfFabZ) of the plasmodial FAS-II system. In vitro antimalarial, antimycobacterial and antibacterial activities of the compounds 1-3 are also reported.

Materials and methods

Plant material, isolation and characterization of compounds 1-3

A. auriculata was collected in Central Greece in 2001 and compounds 1-3 were purified from the organic (EtOAc) extract of the aerial parts of the plant as described (Theodori et al., 2006). Their structures (Fig. 1) were determined by spectroscopic means. The purity of compounds (> 95%) was confirmed by (1) H and [.sup.13] C NMR.


PfFabI enzyme assay

The PfFabI assay was carried out as reported (Tasdemir et al., 2007). Briefly, the compounds were dissolved in DMSO and tested at up to 100 [micro]g/ml concentration in the presence of 1 [micro]g (22 nM) enzyme and 200 [micro]M NADH in 1 ml of 20 mM Hepes pH 7.4 and 150 [micro]M crotonoyl-Coa (substrate). The enoyl-reductase activity of PfFabI was assayed by monitoring the oxidation of NADH to [NAD.sup.+] at 340 nm for 1 min. The initial velocities were determined and [IC.sub.50] values were estimated from graphically plotted dose-response curves. Triclosan was used as positive control (Table 1).
Table 1. Enzyme inhibitory, antimalarial, antimycobacterial and
antibacterial activities of 1-4

Compound PfFabI (a) PfFabG PfFabZ MtFabI
[IC.sub.50] [IC.sub.50] [IC.sub.50] [IC.sub.50] [IC.sub.50]

1 100 100 > 50 4.5
2 20 75 > 50 > 50
3 25 50 > 50 > 75
4 14 (f) 28.3 (f) > 50 (f) n.t

Compound EcFabI P. falciparum M. tuberculosis E. coli
[IC.sub.50] [IC.sub.50] (b) [IC.sub.50] (c) MIC (d) MIC

1 > 50 4.0 20.2 25 (e)
2 > 50 2.0 128.0 51.8 (e)
3 > 50 5.1 119.3 25.8 (e)
4 n.t 23.3 (f) n.t n.t

All [IC.sub.50] and MIC values are in [micro]g/ml. n.t.: not tested due
to low amounts available. Reference compounds:

(a) Triclosan ([IC.sub.50] 0.014 [micro]g/ml).
(b) Artemisinin ([IC.sub.50] 0.0022 [micro]g/ml).
(c) Rifampicin ([IC.sub.50] 0.06 [micro]g/ml).
(d) Streptomycin ([IC.sub.50] 68.6 [micro]g/ml).
(e) These results are from our previous report (Theodori et al., 2006).
(f) These results are from our previous report (Karioti et al., 2007).

MtFabI and EcFabI enzyme assays

The MtFabI and EcFabI enzyme inhibition assays were performed as previously described (Tasdemir et al., 2007). MtFabI (50 nM) and EcFabI (10 nM) were assayed in 30 mM PIPES and 150 mM NaCI buffer at pH 6.8, respectively, using 25 [micro]M 2-dodecenoyl-CoA and 250 [micro]M NADH. Enzyme activity was monitored by following the oxidation of NADH at 340 nm. The initial velocities were determined in triplicates at increasing inhibitor concentration ([I]), and [IC.sub.50] values were calculated by fitting the data to equation y = 100/(1 + [I]/[IC.sub.50]) 1 using Grafit 4.0.

PfFabG and PfFabZ enzyme assays

These assays were also carried out as reported (Tasdemir et al., 2006). FabG assay was performed at 25 [degrees] C in 20 mM Hepes pH 7.0 in the presence of 1 [micro]g (36 nM) enzyme, 100 [micro]M NADPH, 35 mM NaCl and 1% DMSO by following for 1 min the oxidation of NADPH to [NADP.sup.+] at 340 nm using 50 [micro]M acetoacetyl-CoA as substrate. Values for [IC.sub.50] were estimated from graphically plotted dose-response curves while varying the compound concentration. The standard reaction mixture for the FabZ assay consisted of 20 [micro]g (2.9 [micro]M) FabZ in 20 mM Hepes pH 7.4, 150mM NaCl and 1 % DMSO. The decrease in absorption at 263 nm using crotonoyl-CoA as substrate was monitored for 5 min at 25 [degrees] C. The reaction was started with 100 [micro]M crotonoyl-CoA and [IC.sub.50] values of the inhibitors were estimated from graphically plotted dose-response curves.

In vitro assay for Plasmodium falciparum

Antiplasmodial activity was determined using the Kl strain of P. falciparum (resistant to chloroquine and pyrimethamine). A modification of the [[.sup.3]H]-hypox-anthine incorporation assay was used (Matile and Pink, 1990). Briefly, infected human red blood cells in RPMI 1640 medium with 5% Albumax were exposed to serial drug dilutions in microtiter plates. After 48 h of incubation at 37 [degrees] C in a reduced oxygen atmosphere, 0.5 [micro]Ci [.sup.3]H-hypoxanthine was added to each well. Cultures were incubated for a further 24 h before they were harvested onto glass-fiber filters and washed with distilled water. The radioactivity was counted using a BetaplateTM liquid scintillation counter (Wallac, Zurich, Switzerland). The results were recorded as counts per minute per well at each drug concentration and expressed as percentage of the untreated controls. From the sigmoidal inhibition curves [IC.sub.50] values were calculated. Artemisinin was used as reference (Table 1).

In vitro assay for M. tuberculosis

[H.sub.37] Rv strain of M. tuberculosis (ATCC 27294, Rockville, MD) was grown to late log phase in Middlebrook 7H9 broth supplemented with 0.2% v/v glycerol, 0.05% Tween 80 and 10% v/v OADC. Cultures were centrifuged 15 min at 4[degrees]C, washed twice and resuspended in PBS. Suspensions were then passed through an 8 [micro]m filter to remove clumps and aliquots were frozen at--80[degrees]C. The cfu was determined by plating on 7H11 agar plates. The minimum inhibitory concentration (MIC) for M. tuberculosis was assessed by the microplate alamar blue assay as previously described (Collins and Franzblau, 1997). The compounds were dissolved in DMSO and added to culture media to produce a maximum final concentration of l00 [micro]g/ml. Eight two-fold serial dilutions of the test compounds were prepared in Middlebrook 7H12 medium and added to 96-well microplates in a volume of 100 [micro]l. Then M. tuberculosis (100 [micro]l continuing 2 x [l0.sup.4] cfu) was added, yielding a final testing volume of 200 [micro]l. Cultures were incubated for 7 days at 37 [degrees]C after which 12.5 [micro]l of 20% Tween 80, and 20 [micro]l of Alamar Blue were added to cultures. After incubation at 37[degrees]C for 24 h fluorescence was read (ex 530 nm, em 590 nm). The MIC was defined as the lowest concentration effecting a reduction in fluorescence of [greater than or equal to]90% relative to the mean of replicate bacteria-only controls. Rifampicin was used as positive control. Table 1 displays the MIC values of 1-3 against M. tuberculosis whole cells.

Antibacterial assay

The assay and the MIC values of 1-3 against E. coli (ATCC 35218) have been reported previously (Theodori et al., 2006) and shown in Table 1. Streptomycin was used as reference (Table 1).


Our earlier phytochemical studies on A. auriculata (Theodori et al., 2006) afforded the irregular, linear SL anthecotulide (1), as well as two new derivatives thereof, 4-hydroxyanthecotulide (2) and 4-acetoxyanthecotulide (3). Further investigation of the same plant yielded anthecularin (4), a minor, tricyclic SL, which is possibly derived from compound 2 as discussed (Karioti et al., 2007). Anthecularin (4) showed moderate antimalarial activity by inhibiting PfFabI and PfFabG, two key reductases of the PfFAS-II pathway. This activity prompted us to study the inhibitory effects of biosynthetically related sesquiterpenes 1-3 against PfFabI as well as against PfFabG and PfFabZ. In order to assess the selectivity, the compounds were evaluated towards bacterial FabI homologoues from M. tuberculosis and E. coli. These results, as well as the antimalarial, antimycobacterial and antimicrobial effects of the compounds 1-3 are displayed in Table 1. PfFAS-II enzyme inhibitory and antimalarial activities of anthecularin (4) are also included in order to facilitate comparison.

All compounds moderately inhibited the PfFabI enzyme. It was noteworthy that the oxygenated derivatives of anthecotulide (1) were much more potent (I[C.sub.50] of 2: 20 [micro]g/ml; I[C.sub.50] of 3: 25 [micro]g/ml) than the parent compound (1, I[C.sub.50] 100 [micro]g/ml). In contrast, only compound 1 inhibited MtFabI with an I[C.sub.50] value of 4.5 [micro]g/ml, whereas 2 and 3 were inactive against this protein. All there compounds were devoid of inhibitory activity against EcFabI. A similar trend to PfFabI enzyme inhibition was also observed against PfFabG. 4-Acetoxyanthecotulide (3) was the most active SL with an I[C.sub.50] value of 50 [micro]g/ml, followed by 2 ([IC.sub.50] value 75 [micro]g/ml) and 1 (I[C.sub.50] value 100 [micro]g/ml). All three compounds lacked the inhibitory potential against PfFabZ.

When tested against microbial whole cells, all compounds possessed biological activity. In particular, in vitro antimalarial activity against the chloroquine and pyrimethamine-resistant P. falciparum K1 strain was significant. The highest antiplasmodial activity was exerted by compound 2 ([IC.sub.50] 2 [micro]g/ml), followed by 1 and 3 ([IC.sub.50] values 4.0 and 5.1 [micro]g/ml, respectively). Anthecotulide (1) showed the best antimycobacterial activity (MIC 20.2 [micro]g/ml), whereas the activity of 2 and 3 were marginal with MIC values of 128 and 119.3 [micro]g/ml, respectively. Antibacterial effects of compounds 1-3 towards E. coli have been evaluated previosuly (Theodori et al., 2006). As shown in Table 1, compounds 1 and 3 exhibit MIC values around 25 [micro]g/ml, while 2 is less active (MIC value 51.8 [micro]g/ml) against E. coli.


In this study, we have investigated the efficacy of three related linear SLs against FabI enzymes from a range of microbial species, in order to establish the species specificity of these natural compounds. A further aim was to establish a structure-activity-relationship (SAR) among the anthecotulide derivatives (1-3). The compounds were also tested versus two other enzymes involved in the plasmodial FAS-II system, i.e. [beta]-ketoacyl-ACP reductase (PfFabG) and [beta]-hydroxyacyl-ACP deydratase (PfFabZ) to investigate compound selectivity against related enzyme families. In order to validate the inhibitors as potential leads for the development of antimalarial and/or antibacterial agents, their in vitro efficacy on whole cells have also been determined.

The compounds showed clear differentiation in inhibition of Fabl enzymes from different microorganisms. The most dramatic example of species selectivity was observed with anthecotulide (1), which was a much more potent inhibit or MtFabI compared to 2 or 3. Importantly, the ability of 1-3 to inhibit MtFabI correlated with their antimycobacterial activity, suggesting that these compounds target MtFabI in the Mycobacterium. In contrast, the PfFabI inhibitory effect of 1 was weak, and it was inactive against EcFabI. The activity against PfFabG was identical to its pfFabI inhibitory potenital. Hydroxylation of the compound 1 at C-4 as in compound 2, resulted in a five-fold increase in PfFabI and a 25% increase in PfFabG inhibitory activity, but then the MtFabI inhibitory effect was lost. The replacement of the OH group with an acetoxy function at C-4 position, as it is the case with compound 3, only moderately effected PfFabI inhibition, but improved the activity against PfFabG compared to 2. Similar to what was observed for compound 2, an acetoxy substitution at C-4 position abolished the MtFabI inhibitory effect. Thus, it appears that oxygenation of the C-4 position of anthecotulide (1) increases specificity across PfFabI and PfFabG, but is unfavourable for MtFabI inhibition. Notably, the in vitro antimalarial activities of all three compounds are much more potent compared to their PfFAS-II enzyme inhibitory activity, indicating that FAS-II system is not the sole antimalarial target for anthecotulides 1-3, and other mechanisms are also involved. Again, the oxygenation of the C-4 position is not favourable for antimycobacterial activity, as the growth inhibitory activity of compounds 2 and 3 against M. tuberculosis is marginal. Additionally, all compounds arrest the growth of E. coli moderately, but fail to inhibit EcFabI at the highest test concentrations. Thus, the antibacterial activity of the compounds 1-3 against E. coli must arise through other mechanism(s). In contrast, as noted above there is a good correlation between the [IC.sub.50] values for the inhibition of MtFabI and the antimycobacterial activity of 1-3, suggesting that these compounds may represent a profitable starting point for the development of novel antituberculotic chemotherapeutics.

The plants of the family Asteraceae are known to cause contact dermatitis in some individuals (Gordon, 1999). Main allergens involved in these allergic reactions are believed to be the SLs, particularly those containing an [alpha]-methylene-[gamma]-lactone moiety that readily forms covalent bonds with cellular skin proteins, thereby producing antigenic compounds (Barnes et al., 2002). However, this general topic and external effect does not limit the internal use of many plants containing SLs. For example, feverfew, containing the sensitizer parthenolide is widely sold in both registered and unregistered preparations and the incidence of allergic reactions in considered rate (Heptinstall, 1988; Barnes et al., 2002). Anthemis cotula (stinking mayweed, dog fennel) is also a skin sensitizer and this effect has been attributed to anthecotulide (1) (Hausen et al., 1984). At first glance, this might appear as a limiting factor for the development of anthecotulide-type compounds as drug leads. However, there is no detailed pharmacological study as to whether anthecotulide or its derivatives are allergenic internally. Future studies of in uiuo sensitizing effects of anthecotulides will shed light on their potential as new drug leads. With a proper drug formulation, it is very likely that these compounds can be turned into effective medicines, as in the case of parthenolids.


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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), *

(a) Department of Pharamacognosy 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 Based, 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 WCIN 1AX, UK

* Corresponding author. Tel.: +4420 7753 5845; fax: +4420 7753 5909.

E-mail address: deniz. (D. Tasdemir).

0944-7113/$-see front matter [C] 2008 Elsevier GmbH. All rights reserved.

doi: 10.1016/j.phymed.2008.02.018
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Title Annotation:SHORT COMMUNICATION; acyl-carrier-protein
Author:Karioti, Anastasia; Skaltsa, Helen; Zhang, Xujie; Tonge, Peter J.; Perozzo, Remo; Kaiser, Marcel; Fr
Publication:Phytomedicine: International Journal of Phytotherapy & Phytopharmacology
Article Type:Clinical report
Geographic Code:4EUGR
Date:Dec 1, 2008
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