In vitro metabolomic
footprint of the Echinococcus multilocularis
metacestode

Ritler, Dominic; Rufener, Reto; Li, Jia V.; Kämpfer, Urs; Müller, Joachim; Bühr, Claudia; Schürch, Stefan; Lundström‐Stadelmann, Britta

doi:10.1038/s41598-019-56073-y

Cited by 35 publications

(28 citation statements)

References 75 publications

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“…An essential prerequisite for the identification of novel targets is a profound knowledge of the parasite biochemistry and its metabolic requirements. A recent publication by Ritler et al (2019) reported on the molecular footprint of E. multilocularis metacestodes, and by analysing the metabolic host-parasite interface in vitro , a number of potentially targetable metabolic pathways were identified. An important finding was that not only the ubiquitous energy source glucose, but also the amino acid threonine, was consumed by the parasite at high levels.…”

Section: Identification Of Novel Drugs Against Alveolar Echinococcosimentioning

confidence: 99%

Drug repurposing applied: Activity of the anti-malarial mefloquine against Echinococcus multilocularis

Lundström‐Stadelmann

Rufener

Hemphill

2020

International Journal for Parasitology: Drugs and Drug Resistan

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The current chemotherapeutical treatment against alveolar echinococcosis relies exclusively on benzimidazoles, which are not parasiticidal and can induce severe toxicity. There are no alternative treatment options. To identify novel drugs with activity against Echinococcus multilocularis metacestodes, researchers have studied potentially interesting drug targets (e.g. the parasite's energy metabolism), and/or adopted drug repurposing approaches by undertaking whole organism screenings. We here focus on drug screening approaches, which utilize an in vitro screening cascade that includes assessment of the drug-induced physical damage of metacestodes, the impact on metacestode viability and the viability of isolated parasite stem cells, structure-activity relationship (SAR) analysis of compound derivatives, and the mode of action. Finally, once in vitro data are indicative for a therapeutic window, the efficacy of selected compounds is assessed in experimentally infected mice. Using this screening cascade, we found that the anti-malarial mefloquine was active against E. multilocularis metacestodes in vitro and in vivo . To shed more light into the mode of action of mefloquine, SAR analysis on mefloquine analogues was performed. E. multilocularis ferritin was identified as a mefloquine-binding protein, but its precise role as a drug target remains to be elucidated. In mice that were infected either intraperitoneally with metacestodes or orally with eggs, oral treatment with mefloquine led to a significant reduction of parasite growth compared to the standard treatment with albendazole. However, mefloquine was not acting parasiticidally. Assessment of mefloquine plasma concentrations in treated mice showed that levels were reached which are close to serum concentrations that are achieved in humans during long-term malaria prophylaxis. Mefloquine might be applied in human AE patients as a salvage treatment. Future studies should focus on other repurposed anti-infective compounds (MMV665807, niclosamide, atovaquone), which showed stronger in vitro activity against E. multilocularis than mefloquine.

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Section: Identification Of Novel Drugs Against Alveolar Echinococcosimentioning

confidence: 99%

Drug repurposing applied: Activity of the anti-malarial mefloquine against Echinococcus multilocularis

Lundström‐Stadelmann

Rufener

Hemphill

2020

International Journal for Parasitology: Drugs and Drug Resistan

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“…Interestingly, the S. solidus glutamate dehydrogenase isozyme A0A0X3P860 contains the GFGNVG sequence and Glu (278), which are more typical for isoforms that provide the deamination reaction rather than the addition of ammonia (Oliveira et al, 2012;Prakash et al, 2018;Grzechowiak et al, 2020). Therefore, in adult flatworms, this enzyme appears to provide NADPH for redox reactions, probably for the malate dismutation pathway in mitochondria (Smyth and McManus, 2007;Ritler et al, 2019).…”

Section: Discussion Proteomic Changes In S Solidis Are Mostly Energy-relatedmentioning

confidence: 99%

“…In cestodes, glucose oxidation leads either to the formation of lactate, or to the formation of oxaloacetate, and then malate, which is converted into succinate and acetate in mitochondria (CO 2 fixation pathway; malate dismutation pathway) (Smyth and McManus, 2007;Ritler et al, 2019). This cleavage occurs at the level of phosphoenolpyruvate, for which pyruvate kinase (PK) and phosphoenolpyruvate carboxykinase (PEPCK) compete (Das et al, 2015) (Fig.…”

Section: Discussion Proteomic Changes In S Solidis Are Mostly Energy-relatedmentioning

confidence: 99%

Temperature-induced reorganisation of Schistocephalus solidus (Cestoda) proteome during the transition to the warm-blooded host

et al. 2021

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The protein composition of the cestode Schistocephalus solidus was measured in an experiment simulating the trophic transmission of the parasite from a cold-blooded to a warm-blooded host. The first hour of host colonisation was studied in a model experiment, in which sticklebacks Gasterosteus aculeatus infected with S. solidus were heated at 40°C for 1 h. As a result, a decrease in the content of one tegument protein was detected in the plerocercoids of S. solidus. Sexual maturation of the parasites was initiated in an experiment where S. solidus larvae were taken from fish and cultured in vitro at 40°C for 48 h. Temperature-independent changes in the parasite proteome were investigated by incubating plerocercoids at 22°C for 48 h in culture medium. Analysis of the proteome allowed us to distinguish the temperature-induced genes of S. solidus, as well as to specify the molecular markers of the plerocercoid and adult worms. The main conclusion of the study is that the key enzymes of long-term metabolic changes (glycogen consumption, protein production, etc.) in parasites during colonisation of a warm-blooded host are induced by temperature.

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“…Metabolic profiling approaches have been widely used in various studies on diseases caused by flatworms such as Fasciola hepatica and roundworms such as Onchocerca volvulus [ 32 – 35 ]. Nevertheless, reports on the application of the LC–MS/MS-based metabolomics approach in echinococcosis are limited [ 36 ]. In this study, we used a LC–MS/MS system-based metabolomics approach and multivariate statistical analyses to investigate the molecular mechanism of CE and to provide a potential valuable reference for the diagnosis of CE.…”

Section: Introductionmentioning

confidence: 99%

Metabolic profiling of liver and faeces in mice infected with echinococcosis

Zhu

et al. 2021

Parasites Vectors

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Background Echinococcosis is a severe zoonotic parasitic disease which severely affects the health of the hosts. The diagnosis of echinococcosis depends mainly on imaging examination. However, the patient is often in the late stage of the disease when the symptoms appear, thus limiting the early diagnosis of echinococcosis. The treatment and prognosis of the patients are hampered because of long-term asymptomatic latency. Metabolomics is a new discipline developed in the late 1990s. It reflects a series of biological responses in pathophysiological processes by demonstrating the changes in metabolism under the influence of internal and external factors. When the organism is invaded by pathogens, the alteration in the characteristics of metabolites in cells becomes extremely sensitive. Here, we used a metabolomics approach involving liquid chromatography coupled with tandem mass spectrometry (LC–MS/MS) to determine the molecular mechanism of cystic echinococcosis (CE) and to develop an effective method for CE diagnosis. Methods Twenty 8-week-old female BALB/c mice were divided into normal and Echinococcus granulosus infection groups. To develop the E. granulosus infection model, mice were infected with protoscoleces. Six weeks later, the abdomens of the mice showed significant bulging. An LC–MS/MS system-based metabolomics approach was used to analyse the liver and faeces to reveal the metabolic profiles of mice with echinococcosis. Results We found that the metabolism of nucleotides, alkaloids, amino acids, amides, and organic acids in mice is closely interrelated with E. granulosus infection. In the liver, the metabolic pathways of tyrosine and tryptophan biosynthesis; phenylalanine, valine, leucine and isoleucine biosynthesis; and phenylalanine metabolism were notably associated with the occurrence and development of hydatid disease, and in the faeces, pantothenate and CoA biosynthesis are thought to be closely associated with the development of CE. Conclusion The metabolomics approach used in this study provides a reference for a highly sensitive and specific diagnostic and screening method for echinococcosis. Graphic Abstract

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In vitro metabolomic footprint of the Echinococcus multilocularis metacestode

Cited by 35 publications

References 75 publications

Drug repurposing applied: Activity of the anti-malarial mefloquine against Echinococcus multilocularis

Drug repurposing applied: Activity of the anti-malarial mefloquine against Echinococcus multilocularis

Temperature-induced reorganisation of Schistocephalus solidus (Cestoda) proteome during the transition to the warm-blooded host

Metabolic profiling of liver and faeces in mice infected with echinococcosis

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