JAC Advance Access originally published online on April 4, 2006
Journal of Antimicrobial Chemotherapy 2006 57(6):1093-1099; doi:10.1093/jac/dkl117
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In vitro activity of iron-binding compounds against Senegalese isolates of Plasmodium falciparum
1 Unité de Recherche en Biologie et Epidémiologie Parasitaires, Institut de Médecine Tropicale du Service de Santé des Armées Le Pharo, 13998 Marseille, France 2 Institut Fédératif de la Recherche no 48 13385 Marseille, France 3 Service d'Epidémiologie, Institut Pasteur Dakar, Sénégal 4 Laboratoire de Chimie Bioorganique et Bioinorganique, CNRS URA 1384, Institut de Chimie Moléculaire d'Orsay 91405 Orsay, France 5 Département d'Epidémiologie et de Santé Publique, Ecole d'Application du Service de Santé des Armées 94998 Saint Mandé, France 6 UR 077 de Paludologie Afrotropicale, Institut pour la Recherche et le Développement Dakar, Sénégal 7 Unité de Recherche en Physiopathologie et de Pharmacogénétique Parasitaires, Institut de Médecine Tropicale du Service de Santé des Armées Le Pharo, 13998 Marseille, France
*Correspondence address. Unité de Recherche en Biologie et Epidémiologie Parasitaires, Institut de Médecine Tropicale du Service de Santé des Armées, Boulevard Charles Livon, Le Pharo, BP 46, 13998 Marseille, France. Tel: +33-491-150-110; Fax: +33-491-150-164; E-mail: bruno.pradines{at}free.fr
Received 27 September 2005; returned 16 November 2005; revised 9 January 2006; accepted 12 March 2006
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Abstract |
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Objectives: The in vitro activities of FR160, a synthetic catecholate siderophore, and two iron-binding agents, desferrioxamine and doxycycline, were evaluated against Plasmodium falciparum isolates. Correlations between these compounds and standard antimalarial drugs (chloroquine, quinine, amodiaquine, pyronaridine, artemether, artesunate, atovaquone, cycloguanil and pyrimethamine) were assessed to determine any degree of cross-resistance.
Methods: Between October 1997 and February 1998, and September and November 1998, 189 P. falciparum isolates were obtained in Dielmo and Ndiop (Dakar). Their susceptibilities were assessed using an isotopic, microwell format, drug susceptibility test.
Results: The 137 inhibitory concentrations (IC50) values of FR160 ranged from 0.1 to 10 µM and the geometric mean IC50 was 1.48 µM (95% CI = 1.29–1.68 µM). The geometric mean IC50 of doxycycline for 121 isolates was 18.9 µM (95% CI = 16.8–21.3 µM) and that of desferrioxamine for 73 isolates was 20.7 µM (95% CI = 17.3–24.8 µM). FR160 was significantly less active against the chloroquine-resistant isolates (P < 0.0001). The mean IC50s of doxycycline were significantly higher for the chloroquine-susceptible isolates than for the resistant parasites (P = 0.0447). There was a weak correlation between the responses to FR160, desferrioxamine or doxycycline and those to the other antimalarial compounds (r2 < 0.22).
Conclusions: The activities of FR160 and desferrioxamine, determined for P. falciparum clones, were confirmed against 137 isolates. The coefficients of determination between the responses to FR160, doxycycline or desferrioxamine and those to all the antimalarial drugs tested are too weak to suggest cross-resistance. FR160 could be a rationale partner to use in combination with doxycycline.
Keywords: malaria , iron chelation , chemotherapy , antimalarial drugs , Senegal
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New antimalarial drugs are needed to combat the rapid emergence and spread of parasite multidrug resistance. Clinical studies have shown that iron supplementation to iron-deficient individuals causes exacerbation of malaria.1 Iron chelation therapy was considered a suitable treatment for various infectious diseases, including malaria.2,3 Iron is an essential element for growth of all living organisms.4 The metal is needed for catalysis of DNA synthesis and for a variety of enzymes involved in electron transport and energy metabolism. Many compounds have the ability to bind iron. The antimalarial effects of iron chelators,5 antibiotics such as cyclines6,7 and bioflavonoid glycosides8 can be reversed with the addition of iron.
The iron chelator desferrioxamine has been shown to suppress malaria parasite growth both in vitro9,10 and in vivo.11,12 However, the time window of action of desferrioxamine is relatively limited and the antimalarial activity is slow to develop, even after continuous in vitro or in vivo exposure to desferrioxamine.13 In addition, application of desferrioxamine in malaria therapy is greatly limited by its short half-life in plasma (5–10 min) and poor absorption following oral administration.14 Various iron chelators were assessed to improve drug lipophilicity leading to increased access of the drug to intracellular parasites and to a faster speed of action.15,16 In addition, several studies explored the possibility of improving the antimalarial efficacy of iron chelators by using them in various combinations with different speeds of action, stage dependences and degrees of reversibility of effects.17–19 We have shown the in vitro activity of FR160, a catecholate siderophore derived from spermidine, against clones of Plasmodium falciparum.20 FR160 affected the parasites at considerably faster rates and at all stages of parasite growth.3 We have reported that FR160 induced synergic effects in combination with tetracyclines and norfloxacin21 or atovaquone and antagonistic effects with artesunate or dihydroartemisinin.3 FR160 reached and accumulated in P. falciparum erythrocytes and parasites22 and seems to act by the generation of radical species and enhancement of haem-catalysed oxidation of lipid membranes.23
In the past, the use of antibiotics has allowed the control of drug-resistant strains. Thirty years ago, tetracyclines were found to have antimalarial activity.24 Experimental observations obtained in vitro6,25 and in clinical studies26,27 proved the antimalarial activity of doxycycline in prophylaxis. However, a surge in the number of malaria cases within 3 weeks after discontinuing doxycycline prophylaxis is often observed.28,29 Doxycycline failures soon after termination of the drug therapy suggest that doxycycline may have served primarily as a suppressive agent. Because of its pharmacokinetic parameters such as elimination half-life (16 h)29 and slow action that has a delayed effect upon growth and multiplication, which requires prolonged incubation of parasites,6,25 doxycycline should be administered in conjunction with another drug.
The aim of the present study was to confirm the in vitro activity of FR160 against P. falciparum clinical isolates from Senegal and to compare this with that of two compounds that may bind iron, desferrioxamine20 and doxycycline.6,7 Correlations between these compounds with iron-chelating effects and standard antimalarial drugs (chloroquine, quinine, amodiaquine, pyronaridine, artemether, artesunate, atovaquone, cycloguanil and pyrimethamine) were assessed to determine any degree of cross-resistance. Cross-resistance analyses could be helpful to find a rational partner compound with which FR160 and doxycycline can be administered.
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Isolates of P. falciparum
Between October 1997 and February 1998, and September and November 1998, 189 P. falciparum isolates were obtained in Dielmo and Ndiop (280 km south-east of Dakar) in the Fatick region of Senegal. Patients from Dielmo and Ndiop were recruited at home by daily active case detection during a longitudinal study of the mechanisms of protective immunity to malaria.30,31 Venous blood was collected before treatment in Vacutainer® ACD tubes (Becton Dickinson, Rutherford, NJ, USA) and transported at 4°C to our laboratory in Marseille. The project protocol and the objectives were carefully explained to the assembled village population and informed consent was obtained individually from all adults and from the parents of children. The protocol was approved by the Ethics Committee of the Pasteur Institute of Dakar and the Ministère du Plan et de la Coopération and the Ministère de la Recherche Scientifique of Senegal (absence of National Ethics Committee, which was created in 2005). Each year, the project was re-examined by the Conseil de Perfectionnement de l'Institut Pasteur de Dakar and the assembled population of the village and informed consent was individually renewed. Thin blood smears were stained using an RAL® kit (Réactifs RAL, Paris, France) and examined to determine P. falciparum density. Samples with parasitaemia ranging from 0.05% to 6.0% were used to test drug susceptibility. Parasitized erythrocytes were washed three times in RPMI 1640 medium (Invitrogen, Paisley, UK). If parasitaemia exceeded 0.8%, infected erythrocytes were diluted to 0.5–0.8% with uninfected erythrocytes and resuspended in the culture medium to a haematocrit of 1.5%. Susceptibilities to FR160, desferrioxamine, doxycycline, atovaquone, artemether, artesunate, chloroquine, quinine, pyronaridine and amodiaquine were determined after suspension in RPMI 1640 medium and to cycloguanil and pyrimethamine after suspension in RPMI 1640 SP823 with reduced p-aminobenzoic acid (0.5 µg/L) and low folates (10 µg/L) (Invitrogen). The two suspensions were supplemented with 10% human serum and buffered with 25 mM HEPES and 25 mM NaHCO3.
Drugs
The synthesis of FR160 was as described previously.20 Doxycycline hydrochloride, desferrioxamine mesylate, chloroquine diphosphate, quinine hydrochloride, amodiaquine dihydrochloride and pyrimethamine were obtained from Sigma (St Louis, MO, USA), atovaquone from the Wellcome Foundation Ltd (Beckenham, UK), pyronaridine phosphate from the World Health Organization (batch 260642, Geneva), artesunate and artemether from Rhône Poulenc Rorer (Antony, France) and cycloguanil from Zeneca Pharma (Reims, France). Stock solutions were prepared in methanol for FR160, doxycycline, artemether, artesunate, atovaquone, quinine and pyrimethamine, and were prepared in sterile water for desferrioxamine, pyronaridine, chloroquine, amodiaquine and cycloguanil. Two-fold serial dilutions were prepared in sterile water. Final concentrations were distributed in triplicate into Falcon 96-well flat-bottomed plates (Becton Dickinson, Franklin Lakes, NJ, USA). The chloroquine-susceptible D6 P. falciparum clone (Sierra Leone) and the chloroquine-resistant W2 clone (Indochina) were used as references to test each batch of plates. Reference clones were maintained in continuous culture and synchronized twice with sorbitol.32
In vitro assay
For in vitro isotopic microtests, 200 µL/well of the suspension of parasitized erythrocytes was distributed in 96-well plates predosed with antimalarial agents. Parasite growth was assessed by adding 1 µCi of [3H]hypoxanthine with a specific activity of 14.1 Ci/mmol (NEN Products, Dreiech, Germany) to each well. Plates were incubated for 42 h at 37°C in an atmosphere of 10% O2, 6% CO2, 84% N2 and a humidity of 95%. Immediately after incubation the plates were frozen and then thawed to lyse the erythrocytes. The contents of each well were collected on standard filter microplates (UnifilterTM GF/B, Perkin Elmer, Meriden, USA) and washed using a cell harvester (FilterMateTM Cell Harvester, Packard). Filter microplates were dried and 25 µL of scintillation cocktail (MicroscintTM O, Perkin Elmer) was placed in each well. Radioactivity incorporated by the parasites was measured using a scintillation counter (Top CountTM, Perkin Elmer).
The 50% inhibitory concentration (IC50), i.e. the drug concentration corresponding to 50% of the uptake of [3H]hypoxanthine by the parasites in drug-free control wells, was determined by non-linear regression analysis of log-dose/response curves (RiasmartTM, Packard, Meriden, USA). Data were analysed after logarithmic transformation and expressed as the geometric mean IC50, and 95% confidence intervals (95% CI) were calculated (StatViewTM, SAS). The unpaired t-test was used to compare IC50 values from chloroquine-susceptible and chloroquine-resistant isolates. Assessment of FR160, desferrioxamine and doxycycline cross-resistance with the other antimalarial drugs (atovaquone, artemether, artesunate, chloroquine, quinine, amodiaquine, pyronaridine, pyrimethamine and cycloguanil) was estimated by Pearson correlation coefficient (r) and coefficient of determination (r2) (StatViewTM, SAS).
The cut-off value for in vitro resistance to chloroquine was 100 nM. This in vitro threshold value has been defined statistically (>2 SD above the mean).
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The following proportions of isolates were successfully cultured for each drug tested: 137 of 189 for FR160, 147 of 189 for chloroquine, 146 of 189 for pyrimethamine, 144 of 189 for quinine and cycloguanil, 142 of 189 for amodiaquine, 121 of 189 for doxycycline, 73 of 85 for pyronaridine, 73 of 85 for desferrioxamine, 71 of 104 for artemether and artesunate, and 68 of 104 for atovaquone. Average parameter estimates for the 12 compounds against all isolates are given in Table 1.
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The IC50 values for FR160 ranged from 0.1 to 10 µM and the geometric mean IC50 for 137 isolates was 1.48 µM (95% CI = 1.29–1.68 µM). The geometric mean IC50 of doxycycline for 121 isolates was 18.9 µM (95% CI = 16.8–21.3 µM) and that of desferrioxamine for 73 isolates was 20.7 µM (95% CI = 17.3–24.8 µM).
FR160 was significantly less active against the chloroquine-resistant isolates (P < 0.0001) (Table 2). The mean IC50 was significantly higher in the chloroquine-susceptible isolates than in the resistant parasites for doxycycline (P = 0.0447).
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There was a weak correlation between the responses to FR160 (Table 3), desferrioxamine (Table 4) or doxycycline (Table 5) and those to the other antimalarial compounds (r2 < 0.22).
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FR160 is 14-fold more potent than desferrioxamine, our iron chelator reference. Desferrioxamine is known to be active in vitro against P. falciparum with IC50s ranging from 10 to 30 µM,33–36 in rodents,37 in primate models38 and in humans.12,39 In addition to its better activity, FR160 acts on parasites at considerably faster rates and at all stages of parasite growth.5 FR160 is also more potent than the majority of the iron chelators tested in vitro, i.e. reversed siderophores (RSFs) with IC50s ranging from 3 to >100 µM,15,40 salicyaldehyde isonicotinoyl hydrazone (SIH) from 20 to 40 µM,13,19 hydroxypyridinone from 30 to 50 µM,35 aminothiol derivatives from 3 to 8 µM,41 and dexrazoxane with IC50 >200 µM.42 FR160 shows a mean IC50 967-fold greater than that of artesunate, 482-fold greater than that of artemether, 416-fold greater than that of atovaquone, 327-fold greater than that of pyronaridine, 117-fold greater than that of amodiaquine, 19-fold greater than that of chloroquine, 8-fold greater than that of quinine and cycloguanil and 2-fold greater than that of pyrimethamine. Most of these compounds are potent in a low or middle nanomolar range. The in vitro activity of FR160 is in the low micromolar range. A generally agreed upon level of efficacy would be in the low or middle nanomolar range. However, if the mechanisms of action of such a compound are sufficiently new and different from those of the commonly used antimalarial drugs, that compound could warrant further work. Doxycycline, which shows an IC50 13-fold greater than that of FR160, is one of these compounds. Daily doxycycline has been shown to be an effective causal chemoprophylactic in Thailand,43 Indonesia44 and Kenya,45 and is currently one of the recommended chemoprophylactic regimens for travellers or soldiers visiting south-east Asia and Africa.46
The mechanisms of action of FR160 seem to be different from those of used antimalarial drugs. FR160 acts by generation of radical species and enhancement of haem-catalysed oxidation of lipid membranes and neither affects the chemical haem polymerization activity nor the production of haemozoin in P. falciparum parasites,23 while amino-4-quinolines, amino-alcohols, amino-8-quinolines and sesquiterpene lactones inhibit the haem polymerization.47–49 In addition, the ribonucleotide reductase of P. falciparum, a key iron-dependent enzyme in pyrimidine de novo synthesis, could be a target for FR160, as for desferrioxamine.50,51 FR160 is more potent against chloroquine-susceptible parasites than chloroquine-resistant isolates (P < 0.0001). The majority of the drugs tested in this study are less potent against chloroquine-resistant parasites. This observation is similar to that obtained in previous studies between chloroquine-susceptible strains and chloroquine-resistant W2 strains.5,20,22 We have shown that FR160 accumulation in infected erythrocytes was correlated with chloroquine accumulation (r2 = 0.882), in few strains.22 Nevertheless, the hypothesis that correlation between the accumulation values could be ascribed to common mechanisms of uptake is significantly weakened by the finding that pharmacological blockers, which modulate the response to chloroquine, such as verapamil, diltiazem, amiloride or clotrimazole, have no effect on the accumulation of FR160 and antagonize its activity.22
Doxycycline was more potent in vitro against the chloroquine-resistant isolates than against the chloroquine-susceptible isolates. Doxycycline showed an IC50 250-fold greater than that of chloroquine. Nevertheless, this moderate in vitro activity leaves aside effects against pre-erythrocytic stages52,53 and increases after an exposure of 96 h. Several studies demonstrated on clones or isolates that potency was increased by prolonged exposure.6,25,54 In addition, antibiotics that inhibit protein synthesis on 70S ribosomes show marked dependence on O2 exposure in vitro. IC50s at 96 h in high oxygen (15%) and low oxygen (1%) were generally about 100 times and 10 times lower than those observed at 48 h.54 In the present study, experiments were conducted in 10% O2. The use of different in vitro criteria such as O2 tension and time of exposure leads to difficulties when comparing data from different studies. The geometric mean IC50 value of doxycycline for the 121 isolates was 18.9 µM. In previous studies of Thai isolates55 and Cambodian and African strains56 the geometric mean IC50 values for doxycycline were 5.10 and 4.3 µM, respectively. The in vitro assay systems used in these studies (17% O2 and 5% O2) differed from that of our work (10% O2).
A positive correlation between the IC50s of two antimalarial drugs may suggest in vitro cross-resistance or at least common mechanisms of action, but the relationship between in vitro and in vivo resistance depends on the level of resistance and the coefficients of correlation (r) and determination (r2). To involve the same mechanism of action for two compounds, which could induce cross-resistance, the coefficient of correlation must be high, such as for artemether and artesunate (r2 = 0.699) and cycloguanil and pyrimethamine (r2 = 0.780) (not shown). All the coefficients of determination calculated between the responses to FR160, doxycycline or desferrioxamine and that of all the drugs tested are inferior to 0.22, suggesting that <22% of the variations in responses to FR160 are explained by variations in responses to the other drugs. The correlation shown previously between responses to FR160 and chloroquine for four strains (r2 = 0.517),22 is not found again for these 135 isolates. In addition, there is no cross-resistance between the three compounds with the ability to bind iron: FR160, desferrioxamine and doxycycline. Such data could suggest different features in the drug uptake and/or mode of action of FR160, doxycycline and desferrioxamine and the other compounds. It seems that these three agents have different modes of action. FR160 acts by generation of free radical species and enhancement of haem-catalysed oxidation of lipid membranes,25 desferrioxamine acts by inhibition of the ribonucleotide reductase50,51 and doxycycline by inhibition of mitochondrial and apicoplastid ribosomal proteins57,58 and inhibition of the dihydroorotate dehydrogenase.59 Tetracycline acts on the mitochondrion57 and depresses the activity of dihydroorotate dehydrogenase of the pyrimidine pathway in P. falciparum,59 presumably due to the inhibition of enzyme protein synthesis. Doxycycline reduced the levels of malaria nucleoside 5'-triphosphates and deoxynucleoside 5'-triphosphates60 and has shown inhibitory effects against pre-erythrocytic stages.53
The hypothesis of inducing cross-resistance by the use of FR160 or doxycycline is very unlikely. It could be possible to combine FR160 or doxycycline with 1 of the 11 antimalarial drugs tested. These results must be compared with assessment of in vitro drug combinations. FR160/chloroquine and FR160/quinine drug combinations are additive20 while desferrioxamine/chloroquine or desferrioxamine/quinine drug combinations are antagonistic61 or additive.56,62 FR160 also antagonized the effects of primaquine (8-aminoquinoline) and pyronaridine (Mannich base).5
FR160 antagonized the effects of artemisinin derivatives, as desferrioxamine with artemisinin.63 The artemisinin derivatives, such as the iron chelator FR160, act by generation of radical species and enhancement of haem-catalysed oxidation of lipid membranes. Nevertheless, iron is required for the antimalarial activity of artemisinin and its derivatives.63 This is analogous to the Fenton reaction, in which iron catalyses the degradation of hydrogen peroxide and hydroperoxide to produce radicals. Responses to FR160 are not linked to those of doxycycline. We showed previously that FR160 had synergic effects with tetracyclines.21 In addition, the relatively slow antimalarial action of doxycycline suggests that this drug probably needs to be administered in conjunction with a rapidly acting regimen, such as FR160, which is potent after 3 h of exposure, irrespective of the parasite stage.
The in vitro activity of FR160 against all the intraerythrocytic stages, its mechanisms of action that are different from the other antimalarial drugs, the weak correlations or the lack of correlation with the other antimalarial drugs, and its synergic effects with doxycycline or atovaquone are factors that favour the use of FR160 as an antimalarial drug in combination. The efficacy and toxicity of FR160 in animals are being studied.
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There is no conflict of interest. Authors do not own stocks or shares in a company that might be financially affected by the conclusions of this article. The conclusion of this article was not financially affected.
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Acknowledgements |
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We thank F. Ndiaye, Dr F. Diene-Sarr, Dr A. B. Ly, A. Badiane, C. Bouganali, J. Faye, E. H. Mbengue, O. Sarr, G. Ndiaye and B. Thiam for their technical assistance and availability in field work; the staff of Institut de Médecine Tropicale du Service de Santé des Armées (P. Bigot, M. Fortunee, R. Ges, D. Ragot, D. Ramarlah and Y. Trullemans) for the technical support; and the Dielmo and Ndiop populations for their participation. Financial support: this work was supported by la Délégation Générale pour l'Armement (contrat d'objectif no. 9810060) and le Ministère de la Coopération et du Développement.
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