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1.  Correlation between Plasmodium yoelii nigeriensis Susceptibility to Artemisinin and Alkylation of Heme by the Drug 
Evidence of artemisinin (ART) resistance in all of the Greater Mekong Region is currently of major concern. Understanding of the mechanisms of resistance developed by Plasmodium against artemisinin and its derivatives is urgently needed. We here demonstrated that ART was able to alkylate heme in mice infected by the ART-susceptible strain of Plasmodium yoelii nigeriensis, Y-control. After long-term drug pressure, the parasite strain (Y-ART3) was 5-fold less susceptible to ART than Y-control. In the blood of mice infected by Y-ART3, no heme-artemisinin adducts could be detected. After release of ART drug pressure, the parasite strain obtained (Y-REL) regained both drug susceptibility to ART and increased ability to produce covalent heme-artemisinin adducts. The correlation between parasite ART susceptibility and alkylation of heme by the drug confirms that heme or hemozoin metabolism is a key target for efficacy of ART as an antimalarial.
doi:10.1128/AAC.01064-13
PMCID: PMC3719719  PMID: 23752508
2.  Deep-Sea Bioluminescence Blooms after Dense Water Formation at the Ocean Surface 
Tamburini, Christian | Canals, Miquel | Durrieu de Madron, Xavier | Houpert, Loïc | Lefèvre, Dominique | Martini, Séverine | D'Ortenzio, Fabrizio | Robert, Anne | Testor, Pierre | Aguilar, Juan Antonio | Samarai, Imen Al | Albert, Arnaud | André, Michel | Anghinolfi, Marco | Anton, Gisela | Anvar, Shebli | Ardid, Miguel | Jesus, Ana Carolina Assis | Astraatmadja, Tri L. | Aubert, Jean-Jacques | Baret, Bruny | Basa, Stéphane | Bertin, Vincent | Biagi, Simone | Bigi, Armando | Bigongiari, Ciro | Bogazzi, Claudio | Bou-Cabo, Manuel | Bouhou, Boutayeb | Bouwhuis, Mieke C. | Brunner, Jurgen | Busto, José | Camarena, Francisco | Capone, Antonio | Cârloganu, Christina | Carminati, Giada | Carr, John | Cecchini, Stefano | Charif, Ziad | Charvis, Philippe | Chiarusi, Tommaso | Circella, Marco | Coniglione, Rosa | Costantini, Heide | Coyle, Paschal | Curtil, Christian | Decowski, Patrick | Dekeyser, Ivan | Deschamps, Anne | Donzaud, Corinne | Dornic, Damien | Dorosti, Hasankiadeh Q. | Drouhin, Doriane | Eberl, Thomas | Emanuele, Umberto | Ernenwein, Jean-Pierre | Escoffier, Stéphanie | Fermani, Paolo | Ferri, Marcelino | Flaminio, Vincenzo | Folger, Florian | Fritsch, Ulf | Fuda, Jean-Luc | Galatà, Salvatore | Gay, Pascal | Giacomelli, Giorgio | Giordano, Valentina | Gómez-González, Juan-Pablo | Graf, Kay | Guillard, Goulven | Halladjian, Garadeb | Hallewell, Gregory | van Haren, Hans | Hartman, Joris | Heijboer, Aart J. | Hello, Yann | Hernández-Rey, Juan Jose | Herold, Bjoern | Hößl, Jurgen | Hsu, Ching-Cheng | de Jong, Marteen | Kadler, Matthias | Kalekin, Oleg | Kappes, Alexander | Katz, Uli | Kavatsyuk, Oksana | Kooijman, Paul | Kopper, Claudio | Kouchner, Antoine | Kreykenbohm, Ingo | Kulikovskiy, Vladimir | Lahmann, Robert | Lamare, Patrick | Larosa, Giuseppina | Lattuada, Dario | Lim, Gordon | Presti, Domenico Lo | Loehner, Herbert | Loucatos, Sotiris | Mangano, Salvatore | Marcelin, Michel | Margiotta, Annarita | Martinez-Mora, Juan Antonio | Meli, Athina | Montaruli, Teresa | Moscoso, Luciano | Motz, Holger | Neff, Max | Nezri, Emma nuel | Palioselitis, Dimitris | Păvălaş, Gabriela E. | Payet, Kevin | Payre, Patrice | Petrovic, Jelena | Piattelli, Paolo | Picot-Clemente, Nicolas | Popa, Vlad | Pradier, Thierry | Presani, Eleonora | Racca, Chantal | Reed, Corey | Riccobene, Giorgio | Richardt, Carsten | Richter, Roland | Rivière, Colas | Roensch, Kathrin | Rostovtsev, Andrei | Ruiz-Rivas, Joaquin | Rujoiu, Marius | Russo, Valerio G. | Salesa, Francisco | Sánchez-Losa, Augustin | Sapienza, Piera | Schöck, Friederike | Schuller, Jean-Pierre | Schussler, Fabian | Shanidze, Rezo | Simeone, Francesco | Spies, Andreas | Spurio, Maurizio | Steijger, Jos J. M. | Stolarczyk, Thierry | Taiuti, Mauro G. F. | Toscano, Simona | Vallage, Bertrand | Van Elewyck, Véronique | Vannoni, Giulia | Vecchi, Manuela | Vernin, Pascal | Wijnker, Guus | Wilms, Jorn | de Wolf, Els | Yepes, Harold | Zaborov, Dmitry | De Dios Zornoza, Juan | Zúñiga, Juan | Roberts, John Murray
PLoS ONE  2013;8(7):e67523.
The deep ocean is the largest and least known ecosystem on Earth. It hosts numerous pelagic organisms, most of which are able to emit light. Here we present a unique data set consisting of a 2.5-year long record of light emission by deep-sea pelagic organisms, measured from December 2007 to June 2010 at the ANTARES underwater neutrino telescope in the deep NW Mediterranean Sea, jointly with synchronous hydrological records. This is the longest continuous time-series of deep-sea bioluminescence ever recorded. Our record reveals several weeks long, seasonal bioluminescence blooms with light intensity up to two orders of magnitude higher than background values, which correlate to changes in the properties of deep waters. Such changes are triggered by the winter cooling and evaporation experienced by the upper ocean layer in the Gulf of Lion that leads to the formation and subsequent sinking of dense water through a process known as “open-sea convection”. It episodically renews the deep water of the study area and conveys fresh organic matter that fuels the deep ecosystems. Luminous bacteria most likely are the main contributors to the observed deep-sea bioluminescence blooms. Our observations demonstrate a consistent and rapid connection between deep open-sea convection and bathypelagic biological activity, as expressed by bioluminescence. In a setting where dense water formation events are likely to decline under global warming scenarios enhancing ocean stratification, in situ observatories become essential as environmental sentinels for the monitoring and understanding of deep-sea ecosystem shifts.
doi:10.1371/journal.pone.0067523
PMCID: PMC3707865  PMID: 23874425
3.  Antischistosomal Activity of Trioxaquines: In Vivo Efficacy and Mechanism of Action on Schistosoma mansoni 
Schistosomiasis is among the most neglected tropical diseases, since its mode of spreading tends to limit the contamination to people who are in contact with contaminated waters in endemic countries. Here we report the in vitro and in vivo anti-schistosomal activities of trioxaquines. These hybrid molecules are highly active on the larval forms of the worms and exhibit different modes of action, not only the alkylation of heme. The synergy observed with praziquantel on infected mice is in favor of the development of these trioxaquines as potential anti-schistosomal agents.
Author Summary
Schistosomiasis is a tropical disease affecting more than 200 million people throughout the sub-tropical and tropical world. The treatment and control of schistosomiasis rely on the use of a single drug, the praziquantel and no vaccine is available. However, schistosome species with low sensitivity or resistance to praziquantel have been identified in several countries. It is an urgent need to develop new drugs against this parasite. In this context, our study reports the activity the trioxaquine PA1259. PA1259 is an hybrid drug containing two pharmacophores within a single molecule: a trioxane and an aminoquinoline. Initially developed against malaria, the trioxaquines target the heme a disposal product resulting from the digestion of the hemoglobin. The first action of the trioxaquine is an alkylation of the heme with the trioxane entity, and the second action is stacking with the heme due to the aminoquinoline moiety. In this study we show that this new drug is active in vitro against all schistosome stages (cercariae, schistosomule and adult). The PA1259 is also active in vivo and shows synergistic action in association with praziquantel. This opens the route to an efficient bitherapy of a highly neglected disease.
doi:10.1371/journal.pntd.0001474
PMCID: PMC3279339  PMID: 22348155
4.  Trioxaquine PA1259 Alkylates Heme in the Blood-Feeding Parasite Schistosoma mansoni▿ 
Trioxaquine PA1259 is an efficient drug on larval- and adult-stage schistosomes, able to alkylate heme inside worms treated with it, leading to the formation of covalent heme-drug adducts. Such a mechanism, similar to one reported for other trioxaquines in Plasmodium, indicates that heme may be a common target of these trioxane-based drugs in different blood-feeding parasites.
doi:10.1128/AAC.00082-11
PMCID: PMC3088258  PMID: 21300841
5.  In Vitro Activities of Trioxaquines against Schistosoma mansoni▿  
Antimicrobial Agents and Chemotherapy  2009;53(11):4903-4906.
We report the in vitro activities of trioxaquines against larval and adult-stage schistosomes at 5 and 50 μg/ml, respectively. Such activities are equivalent to that of praziquantel, the major and rather unique drug currently used for the treatment of schistosomiasis. In this range of concentrations, artemisinin derivatives (artesunate and artemether) have no activity.
doi:10.1128/AAC.00640-09
PMCID: PMC2772302  PMID: 19596887
6.  The Antimalarial Trioxaquine DU1301 Alkylates Heme in Malaria-Infected Mice▿  
The in vivo alkylation of heme by the antimalarial trioxaquine DU1301 afforded covalent heme-drug adducts that were detected in the spleens of Plasmodium sp.-infected mice. This result indicates that the alkylation capacities of trioxaquines in mammals infected with Plasmodium strains are similar to that of artemisinin, a natural antimalarial trioxane-containing drug.
doi:10.1128/AAC.00165-08
PMCID: PMC2493093  PMID: 18559651
7.  Trioxaquines Are New Antimalarial Agents Active on All Erythrocytic Forms, Including Gametocytes▿  
Malaria is the third most significant cause of infectious disease in the world. The search for new antimalarial chemotherapy has become increasingly urgent due to parasite resistance to classical drugs. Trioxaquines are synthetic hybrid molecules containing a trioxane motif (which is responsible for the antimalarial activity of artemisinin) linked to an aminoquinoline entity (which is responsible for the antiplasmodial properties of chloroquine). These trioxaquines are highly potent against young erythrocytic stages of Plasmodium falciparum and exhibit efficient activity in vitro against chloroquine-sensitive and -resistant strains of P. falciparum (50% inhibitory concentration, 4 to 32 nM) and are also active in vivo against P. vinckei petteri and P. yoelii nigeriensis in suppressive and curative murine tests. The trioxaquine DU1302 is one of these promising antimalarial agents. The present study confirms the absence of toxicity of this drug on cell lines and in a mice model. Moreover, DU1302 exhibits potent activity against gametocytes, the form transmitted by mosquitoes, as killing of the gametocytes is essential to limit the spread of malaria. The ease of chemical synthesis of this trioxaquine prototype should be considered an additional advantage and would make these drugs affordable without perturbations of the drug supply.
doi:10.1128/AAC.00967-06
PMCID: PMC1855510  PMID: 17242150
8.  In Vitro Activities of DU-1102, a New Trioxaquine Derivative, against Plasmodium falciparum Isolates 
The antimalarial trioxaquine derivative DU-1102, synthesized by covalent linkage between aminoquinoline and trioxane moieties, was highly active against Cameroonian isolates (mean 50% inhibitory concentration of 43 nmol/liter) of Plasmodium falciparum. There was no correlation between the responses to DU-1102 and chloroquine and only a low correlation between the responses to DU-1102 and pyrimethamine, suggesting an independent mode of action of the trioxaquine against the parasites.
doi:10.1128/AAC.45.6.1886-1888.2001
PMCID: PMC90564  PMID: 11353644
9.  In Vitro and In Vivo Potentiation of Artemisinin and Synthetic Endoperoxide Antimalarial Drugs by Metalloporphyrins 
Antimicrobial Agents and Chemotherapy  2000;44(10):2836-2841.
The in vitro potentiation of artemisinin by synthetic manganese porphyrin complexes has been recently reported (F. Benoit-Vical, A. Robert, and B. Meunier, Antimicrob. Agents Chemother. 43:2555–2558, 1999). Since the activity of artemisinin and synthetic antimalarial endoperoxides is related to their interaction with heme (S. R. Meshnick, A. Thomas, A. Ranz, C. M. Xu, and H. Z. Pan, Mol. Biochem. Parasitol. 49:181–190, 1991), an improvement of their efficiency may be expected in the presence of a synthetic metalloporphyrin having the same activating role as endogenous heme. With the aim to boost the activity of antimalarial endoperoxide drugs, we were thus led to evaluate the in vitro and in vivo potentiation of natural and synthetic drugs of this family by a nontoxic and cheap metalloporphyrin. The potentiation of artemisinin, β-artemether, and arteflene (Ro 42-1611) by synthetic heme models is reported. In vitro studies on the chloroquine-resistant Plasmodium falciparum FcB1-Columbia strain indicate a synergistic effect of the manganese complex of meso-tetrakis(4-sulfonatophenylporphyrin) (Mn-TPPS) on the activity of artemisinin or β-artemether, whereas this heme model has no influence on the activity of arteflene. A significant synergistic effect on rodent malaria was also observed in vivo between artemisinin and Mn-TPPS using Plasmodium vinckei petteri strain.
PMCID: PMC90158  PMID: 10991867
10.  Potentiation of Artemisinin Activity against Chloroquine-Resistant Plasmodium falciparum Strains by Using Heme Models 
Antimicrobial Agents and Chemotherapy  1999;43(10):2555-2558.
The influence of different metalloporphyrin derivatives on the antimalarial activity of artemisinin was studied with two chloroquine-resistant strains of Plasmodium falciparum (FcB1-Colombia and FcM29-Cameroon) cultured in human erythrocytes. This potentiation study indicates that the manganese complex of meso-tetrakis(4-sulfonatophenyl)porphyrin has a significant synergistic effect on the activity of artemisinin against both Plasmodium strains.
PMCID: PMC89520  PMID: 10508044

Results 1-10 (10)