Comparative study of the effects of artemether and artesunate on juvenile and adult Schistosoma mansoni in experimentally infected mice

Artemether and artesunate, derivatives of the antimalarial artemisinin, also exhibit antischistosomal properties. There is a need to assess comparatively the activity of both compounds against different developmental stages of schistosome parasites. Since artemisinin derivatives will be increasingly used to treat malaria, it is important to study the effects of 7-day monotherapy regimens on schistosome infections. We carried out experiments with mice, infected with juvenile or adult Schistosoma mansoni, and treated with artemether or artesunate at various doses and regimens including those currently used for monotherapy of malaria. Three doses of artemether, at concentrations of 150 or 300 mg/kg, administered to mice with juvenile S. mansoni resulted in worm reductions of 88-97%, which were significantly higher than the 67-77% obtained with artesunate (P < 0·05). Total concentrations of 600 or 800 mg/kg artemether, administered over 2 or 4 consecutive days to mice with adult S. mansoni, reduced the worm burden significantly by 46-51% (P < 0·05). The reduction of the worm burden observed with artesunate was considerably lower, 24-33%, and not significant when compared with untreated control mice. Seven-day monotherapy regimens of artemether or artesunate given at different concentrations to mice with adult S. mansoni showed total worm reductions of 53-61% or 34-49%, respectively. We conclude that artemether and artesunate are efficacious antischistosomal agents, with artemether displaying consistently higher activities. Our findings may contribute to the current strategic discussions on the effect and use of artemisinin derivatives against schistosomes when they are used in malaria chemotherapy in areas of co-endemicity of both parasite

Artemether administered together with haemin damages schistosomes in vitro

We conducted experiments in vitro to assess the effect of artemether in combination with haemin on adult Schistosoma japonicum, S. mansoni and S. haematobium. When schistosomes were maintained in a medium containing artemether at concentrations of 20 μg/mL or less for 72 h, no apparent effect on the schistosomes was seen. When the medium contained 50 or 100 μg/mL haemin as well as artemether, the schistosomes showed decreased motor activity 2-24 h after exposure, which was followed by the staining of the whole worm body a reddish-yellow colour, dilatation of the intestine, and extensive vesiculation of the tegument. Some of the schistosomes died 24 h after exposure, and almost all died within 48-72 h. When schistosomes were exposed to the same concentrations of haemin alone, they were stained a light yellow colour but there was no apparent effect on their survival. Our findings suggest that artemether interacts with haemin to exert a toxic effect on the worms, which might be of importance in the further elucidation of the mechanism of action of artemether on schistosome

Selection and reversal of Plasmodium berghei resistance in the mouse model following repeated high doses of artemether

Artemether, a derivative of artemisinin, is effectively used for the treatment of malaria without any clinically relevant resistance to date. Artemether has also been developed as an antischistosomal agent, exhibiting highest activity against immature parasites. Here, we employ a rodent model and investigate whether the proposed artemether treatment schedule to prevent schistosome-attributable morbidity might select for Plasmodium berghei resistance. Mice infected with an ANKA strain of P. berghei were treated with artemether at either 47mg/kg or 300mg/kg. Once every 7-10days, parasitized erythrocytes were passed to the next group of mice, receiving the same doses of artemether, for 50passages. Resistance development was slow but increased considerably over the final ten passages. At the higher dose of artemether, the indices of resistance were4.8 and8.8 after 40and 50passages, respectively. Importantly, resistance was unstable, since sensitivity reverted to near-normal after five passages without drug pressure. A moderate index of P. berghei resistance and no apparent reversibility was found in comparative experiments employing pyronaridine. In conclusion, the pace of resistance development in P. berghei to repeated high doses of artemether is slow and reversibl

Synthesis and Antimalarial Activity of 11 Dispiro-1,2,4,5-tetraoxane Analogues of WR 148999. 7,8,15,16-Tetraoxadispiro[5.2.5.2]hexadecanes Substituted at the 1 and 10 Positions with Unsaturated and Polar Functional Groups

Eleven novel dispiro-1,2,4,5-tetraoxanes 3 bearing unsaturated and polar functional groups were designed to enhance the oral antimalarial activity of the prototype tetraoxane 2 (WR 148999). With the exception of 3g and 3h, tetraoxanes 3 were available via the peroxidation of corresponding cyclohexanone derivatives in H2SO4/CH3CN. Tetraoxanes 3g and 3h were prepared by hydrolysis of ester tetraoxanes 3e and 3i, respectively. Five of the 11 tetraoxanes were inactive, but six tetraoxanes had IC50 values of 6-26 nM against the K1 and NF54 strains of Plasmodium falciparum compared to corresponding IC50 values of 28 and 39 nM for 2, and 10 and 12 nM for artemisinin (1). Ester tetraoxane 3e was the most active in vitro, some 2-fold more potent than 1. However, none of the six tetraoxanes active in vitro were as effective as either 1 or 2 in vivo; at single doses of 100 mg/kg most possessed little to no vivo activity in mice infected with Plasmodium berghei. Unsaturated tetraoxane 3a was uniquely more active when administered per os (po) than subcutan (sc). For this series of tetraoxanes, the discrepancy between vitro and vivo activities underscores the limitations of conclusions drawn solely from in vitro antimalarial data and illustrates a practical benefit of complementary single-dose in vivo antimalarial screens

Antifungal lipopeptides from Bacillus strains isolated from rhizosphere of Citrus trees

peer reviewedThe microbial ecology within the rhizosphere of Tylenchulus semipenetrans-infected Citrus L. trees was examined. Sixty bacterial strains were obtained from the roots of infected trees and from the eggs of T. semipenetrans. Among these strains some were obtained from the agar plates of two nematophagous fungi, Dactylellina gephyropaga (Drechsler) Ying Yang & Xing Z. Liu and Arthrobotrys conoides Drechsler. Bacterial strains were identified using 16S rDNA, gyrA and rpoB genes sequence analysis. Bacterial strains identified as Bacillus spp. were examined for their ability to synthesize surfactin, iturin, fengycin, kurstakin and bacillomycin using PCR amplification and sequencing of the encoding genes. Additionally, Bacillus strains were screened for their antifungal activity against F. solani, D. gephyropaga and A. conoides using the dual culture technique. Lipopeptide from whole cells and from supernatants of Bacillus spp. were screened using MALDI-TOF-MS analysis. The majority of the identified bacterial strains belong to the genus Bacillus with the predominance of B. cereus, B. thuringiensis, B. pumilus and B. subtilis. A total of fifteen Bacillus strains demonstrated an antifungal activity against F. solani, D. gephyropaga and A. conoides with the strongest effect found in B. amyloliquefaciens. The analysis of lipopeptides showed a high diversity of molecules, including majorly iturin C, bacillomycin D, fengycin A/B and Kurstakin found especially in B. subtilis strains. Moreover, MALDI-TOF-MS analysis showed that the responsible antibiotics for the antifungal Bacillus strains were associated with the presence of Surfactins/Pumilacidin and Fengycin A/B. Our results demonstrated the wide diversity of lipopeptides among Bacillus strains associated with citrus rhizosphere and demonstrated their antifungal ability. Our results extend the importance of Bacillus strains as potential candidates for antimicrobial activities due to their ability to synthesize and secrete cyclic lipopeptides

Lipopeptide biodiversity in antifungal Bacillus strains isolated from Algeria

Several Bacillus strains have been well studied for their ability to control soil-borne plant diseases. This property is linked to the production of several families of lipopeptides. Depending of their structure, these compounds show antifungal and/or plant systemic resistance inducing activities. In this work, the biodiversity of lipopeptides produced by different antifungal Bacillus strains isolated from seeds, rhizospheric, and non-rhizospheric soils in Algeria was analyzed. Sixteen active strains were characterized by PCR for their content in genes involved in lipopeptide biosynthesis and by MALDI-ToF for their lipopeptide production, revealing a high biodiversity of products. The difficulty to detect kurstakin genes led us to design two new sets of specific primers. An interesting potential of antifungal activity and the synthesis of two forms of fengycins differing in the eighth amino acid (Gln/Glu) were found from the strain 8. Investigation of its genome led to the finding of an adenylation domain of the fengycin synthetase predicted to activate the glutamate residue instead of the glutamine one. According to the comparison of both the results of MALDI-ToF-MS and genome analysis, it was concluded that this adenylation domain could activate both residues at the same time. This study highlighted that the richness of the Algerian ecosystems in Bacillus strains is able to produce: surfactin, pumilacidin, lichenysin, kurstakin, and different types of fengycins. © 2018 Springer-Verlag GmbH Germany, part of Springer Natur

Reply to: Ultrafast evolution and transient phases of a prototype out-of-equilibrium Mott-Hubbard material

International audienceReplying to D. Moreno-Mencía et al. Nature Communicationshttps://doi.org/10.1038/s41467-019-11743-3 (2019)