PfMFR3: A multidrug-resistant modulator in Plasmodium falciparum

In malaria, chemical genetics is a powerful method for assigning function to uncharacterized genes. MMV085203 and GNF-Pf-3600 are two structurally related napthoquinone phenotypic screening hits that kill both blood- and sexual-stag

Reaction hijacking inhibition of Plasmodium falciparum asparagine tRNA synthetase

Malaria poses an enormous threat to human health. With ever increasing resistance to currently deployed drugs, breakthrough compounds with novel mechanisms of action are urgently needed. Here, we explore pyrimidine-based sulfonamides as a new low molecular weight inhibitor class with drug-like physical parameters and a synthetically accessible scaffold. We show that the exemplar, OSM-S-106, has potent activity against parasite cultures, low mammalian cell toxicity and low propensity for resistance development. In vitro evolution of resistance using a slow ramp-up approach pointed to the Plasmodium falciparum cytoplasmic asparaginyl-tRNA synthetase (PfAsnRS) as the target, consistent with our finding that OSM-S-106 inhibits protein translation and activates the amino acid starvation response. Targeted mass spectrometry confirms that OSM-S-106 is a pro-inhibitor and that inhibition of PfAsnRS occurs via enzyme-mediated production of an Asn-OSM-S-106 adduct. Human AsnRS is much less susceptible to this reaction hijacking mechanism. X-ray crystallographic studies of human AsnRS in complex with inhibitor adducts and docking of pro-inhibitors into a model of Asn-tRNA-bound PfAsnRS provide insights into the structure-activity relationship and the selectivity mechanism.</p

Reaction hijacking inhibition of Plasmodium falciparum asparagine tRNA synthetase

Malaria poses an enormous threat to human health. With ever increasing resistance to currently deployed drugs, breakthrough compounds with novel mechanisms of action are urgently needed. Here, we explore pyrimidine-based sulfonamides as a new low molecular weight inhibitor class with drug-like physical parameters and a synthetically accessible scaffold. We show that the exemplar, OSM-S-106, has potent activity against parasite cultures, low mammalian cell toxicity and low propensity for resistance development. In vitro evolution of resistance using a slow ramp-up approach pointed to the Plasmodium falciparum cytoplasmic asparaginyl-tRNA synthetase (PfAsnRS) as the target, consistent with our finding that OSM-S-106 inhibits protein translation and activates the amino acid starvation response. Targeted mass spectrometry confirms that OSM-S-106 is a pro-inhibitor and that inhibition of PfAsnRS occurs via enzyme-mediated production of an Asn-OSM-S-106 adduct. Human AsnRS is much less susceptible to this reaction hijacking mechanism. X-ray crystallographic studies of human AsnRS in complex with inhibitor adducts and docking of pro-inhibitors into a model of Asn-tRNA-bound PfAsnRS provide insights into the structure-activity relationship and the selectivity mechanism

Reaction hijacking inhibition of Plasmodium falciparum asparagine tRNA synthetase

Malaria poses an enormous threat to human health. With ever increasing resistance to currently deployed drugs, breakthrough compounds with novel mechanisms of action are urgently needed. Here, we explore pyrimidine-based sulfonamides as a new low molecular weight inhibitor class with drug-like physical parameters and a synthetically accessible scaffold. We show that the exemplar, OSM-S-106, has potent activity against parasite cultures, low mammalian cell toxicity and low propensity for resistance development. In vitro evolution of resistance using a slow ramp-up approach pointed to the Plasmodium falciparum cytoplasmic asparaginyl-tRNA synthetase (PfAsnRS) as the target, consistent with our finding that OSM-S-106 inhibits protein translation and activates the amino acid starvation response. Targeted mass spectrometry confirms that OSM-S-106 is a pro-inhibitor and that inhibition of PfAsnRS occurs via enzyme-mediated production of an Asn-OSM-S-106 adduct. Human AsnRS is much less susceptible to this reaction hijacking mechanism. X-ray crystallographic studies of human AsnRS in complex with inhibitor adducts and docking of pro-inhibitors into a model of Asn-tRNA-bound PfAsnRS provide insights into the structure-activity relationship and the selectivity mechanism

Effet de la combinaison de la lombrifiltration et du lagunage à macrophytes sur le recyclage des effluents sur le site d élevage

Wastewater from animal production can pollute soil, water and air. The Experimental Station of Guernevez uses an integrated system to reduce the pollution effects and to improve the recycling of water and nutrients. It associates a pig house with manure flushing, a screen, a vermifilter, lagoons and constructed wetlands. Our results showed the effect of recycling on the stoechiometry of chemical elements in the recycled liquid. The gaseous emission of the vermifiltre are minimised when the earthworm population is maximised. The sink of methane by vermifilter was confirmed. These results indicate that the earthworm abundance could be proposed as a bioindicator of low energy and low emissions in manure transforming systems. Evolution of chemical elements in each part of system indicated that the stoechiometry of nutrients should change in agricultural systems with increased recycling efficiency.Les effluents liquides de la production animale peuvent polluer le sol, l'eau et l'air. La station Expérimental de Guernevez utilise un système intègré pour réduire les pollutions et améliorer le recyclage de l'eau et des nutriments. Il associe à une porcherie avec rinçage des déjections par chasse d'eau, un tamis, un lombrifiltre, des lagunes et des marais filtrants. Nos résultats montrent l'effet du recyclage sur la stoechiométrie des éléments chimiques du liquide. Les émissions de gaz du lombrifiltre sont minimisées quand la population lombricienne est maximisée. Le puit de méthane par le lombrifiltre a été confirmé. Ces résultats indiquent que l'abondance de vers de terre peut être employée comme bio indicateur de faibles émissions dans les systèmes de transformation des effluents. L'évolution des éléments chimiques aux chaque partie du système indique que la stoechiométrie des nutriments devrait changer dans les milieux agricoles et probablement dans les productions où l'efficacité du recyclage est augmentée.RENNES1-BU Sciences Philo (352382102) / SudocSudocFranceF

Earthworm effects on gaseous emissions during vermifiltration of pig fresh slurry.

International audienceTreatment of liquid manure can result in the production of ammonia, nitrous oxide and methane. Earthworms mix and transform nitrogen and carbon without consuming additional energy. The objective of this paper is to analyse whether earthworms modify the emissions of NH3, N2O, CH4 and CO2 during vermifiltration of pig slurry. The experiment used mesocosms of around 50 L, made from a vermifilter treating the diluted manure of a swine house. Three levels of slurry were added to the mesocosms, with or without earthworms, during one month, in triplicate. Earthworm abundance and gas emissions were measured three and five times, respectively. There was a decrease in emissions of ammonia and nitrous oxide and a sink of methane in treatments with earthworms. We suggest that earthworm abundance can be used as a bioindicator of low energy input, and low greenhouse gas and ammonia output in systems using fresh slurry with water recycling

Optimal transfer between extensive wastewater treatment systems combining vermifiltration, macrophyte lagoons and constructed wetlands.

communication oraleInternational audienc

Optimal transfer between extensive wastewater treatment systems combining vermifiltration, macrophyte lagoons and constructed wetlands.

communication oraleInternational audienc

Design of an integrated piggery system with recycled water, biomass production and water purification by vermiculture, macrophyte ponds and constructed wetlands.

communication oral