Activity of Thymus capitatus essential oil components against in vitro cultured Echinococcus multilocularis metacestodes and germinal layer cells

Hizem, Amani; Lundström‐Stadelmann, Britta; M’rad, Selim; Souiai, Sawssen; Jannet, Hichem Ben; Flamini, Guido; Ascrizzi, Roberta; Ghédira, Kamel; Babba, Hamouda; Hemphill, Andrew

doi:10.1017/s0031182019000295

Cited by 10 publications

(3 citation statements)

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“…Nevertheless, such drugs are a promising starting point for screening approaches with limited resources, and potentially allow to gain more insights about their possible modes of action and thus potentially valuable targets where research should be focused. Most studies on drug repurposing against AE evaluated an overall relatively small number of compounds, including anti-cancer compounds ( Naguleswaran et al, 2006 ; Gelmedin et al, 2008 , 2010 ; Spicher et al, 2008a ; Hübner et al, 2010 ; Hemer and Brehm, 2012 ; Schubert et al, 2014 ; Huang et al, 2018 ; Joekel et al, 2018 ; Förster et al, 2019 ), anti-infective drugs ( Reuter et al, 2003 , 2006 ; Stettler et al, 2003 ; Spicher et al, 2008b ; Stadelmann et al, 2010 , 2011 ; Küster et al, 2011 , 2014a , 2014b , 2015 ; Rufener et al, 2018a , 2018b ), immunotherapeutics ( Emery et al, 1998 ; Pfister et al, 1989 ; Godot et al, 2003 ; Boubaker et al, 2015 ; Wang et al, 2018 ; Jebbawi et al ), and natural products ( Albani Clara and Elissondo María, 2014 ; Albani et al, 2015 ; Yuan et al, 2016 ; Hizem et al, 2019 ). In the following sections, we will focus more on anti-infective drugs, and in particular on the group of anti-malarials.…”

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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“…To date, only few studies applied plant extracts or products against E. multilocularis : thymol, as major component of the essential oils from Thymus vulgaris and Origanum vulgare, and anacardic acid from Brazilian cashew-nut shell liquid were successfully tested against AE in mice [ 27 , 28 ]. Ampelopsin extracted from moyeam, anacardic acid from Brazilian cashew-nut shell liquid, and Thymus capitatus essential oil exhibited in vitro activity against E. multilocularis metacestodes [ 28 , 29 , 30 ]. A larger number of compounds have been assessed for activity against the closely related parasite E. granulosus [ 31 ].…”

Section: Discussionmentioning

confidence: 99%

Maca against Echinococcosis?—A Reverse Approach from Patient to In Vitro Testing

et al. 2021

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Drug-based treatment of alveolar echinococcosis (AE) with benzimidazoles is in most cases non-curative, thus has to be taken lifelong. Here, we report on a 56-year-old male AE patient who received standard benzimidazole treatment and biliary plastic stents, and additionally self-medicated himself with the Peruvian plant extract Maca (Lepidium meyenii). After 42 months, viable parasite tissue had disappeared. Based on this striking observation, the anti-echinococcal activity of Maca was investigated in vitro and in mice experimentally infected with Echinococcus multilocularis metacestodes. Albendazole (ABZ)-treated mice and mice treated with an ABZ+Maca combination exhibited a significantly reduced parasite burden compared to untreated or Maca-treated mice. As shown by a newly established UHPLC-MS/MS-based measurement of ABZ-metabolites, the presence of Maca during the treatment did not alter ABZ plasma levels. In vitro assays corroborated these findings, as exposure to Maca had no notable effect on E. multilocularis metacestodes, and in cultures of germinal layer cells, possibly unspecific, cytotoxic effects of Maca were observed. However, in the combined treatments, Maca inhibited the activity of ABZ in vitro. While Maca had no direct anti-parasitic activity, it induced in vitro proliferation of murine spleen cells, suggesting that immunomodulatory properties could have contributed to the curative effect seen in the patient.

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“…In the study by Hizem et al (2019), the essential oil of Thymus capitatus, seven defined fractions (F1-F7) obtained from silica gel chromatography and several pure essential oil components were evaluated with respect to in vitro activities against E. multilocularis metacestodes and in vitro cultured germinal layer cells. Measurements of metacestode viability and transmission electron microscopy demonstrated that exposure to essential oil, F2 and F4 impaired metacestode viability.…”

Section: Natural Products For the Treatment Of Alveolar And Cystic Echinococcosismentioning

confidence: 99%

Echinococcus: the model cestode parasite

Hemphill

Lundstroem-Stadelmann

2021

Parasitology

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Cestodes are important endoparasitic organisms, some of which are responsible for serious zoonotic diseases. The most severe diseases are inflicted by the larval stages (metacestodes) of Echinococcus multilocularis and E. granulosus sensu lato (s. l.), which are the causative agents of alveolar (AE) and cystic echinococcosis (CE), respectively. Another member of the Taeniidae family, Taenia solium, has also a prominent role as the causative agent of cysticercosis, with a special importance for neurocysticercosis (NC). The adult-stages of these parasites colonialize the intestine of their definitive hosts, which are foxes and dogs for E. multilocularis, canines for E. granulosus and humans for T. solium. In the intestine of the definitive host, selfor cross-fertilization of adults leads to the production of eggs which contain a zygote, eventually forming a pre-larval stage (oncosphere), which is then accidentally ingested by an intermediate host. CE and AE have been historically considered as food-and water-borne infections, with more recent evidence also pointing to the importance of hand-to-mouth transmission, and they are ranked as the most important foodborne parasites worldwide (Tamarozzi et al. 2020;Torgerson et al. 2020). For Echinococcus spp. and T. solium, several mammalian species can be infected as intermediate hosts, including humans, which act as dead-end hosts for E. granulosus and E. multilocularis. Within their intermediate hosts, the parasite larvae are usually targeted to distinct compartments or organs, such as the liver in most cases for E. multilocularis infections or liver and lungs for E. granulosus. In the case of T. solium infections, the most serious consequences occur upon invasion of the central nervous system, which less commonly also can be caused by Echinococcus spp. There, development into the larval metacestode (Echinococccus spp.) or cysticercus (T. solium) stage takes place, which causes disease due to expansion, extensive proliferation and/or inflammatory reactions on part of the host. Besides Echinococcus spp. and Taenia spp., there are a number of other, albeit less prominent, cestodes that exhibit a considerable zoonotic potential. A more recently, identified cestode causing disease in humans was identified in human cases in North America, causing systemic infection of organs and blood vessels (Deplazes et al. 2019). Metacestodes exhibited molecular hallmarks that resembled, but were clearly distinct from, Vesteria mustelae. Vesteria mustelae parasitizes weasels and has not been demonstrated to be zoonotic, indicating that previously unrecognized human pathogenic cestodes species with still unknown potential animal hosts exist (Deplazes et al. 2019). Other species causing disease in humans include Hymenolepis and Dibothriocephalus, but also Bertiella, Dipylidium, Raillietina, Inermicapsifer and Mesocestoides. As indicated in a recently published review, the true clinical significance of these less prominent tapeworms is not well known, as they are often more difficult to iden...

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Activity of Thymus capitatus essential oil components against in vitro cultured Echinococcus multilocularis metacestodes and germinal layer cells

Cited by 10 publications

References 46 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

Maca against Echinococcosis?—A Reverse Approach from Patient to In Vitro Testing

Echinococcus: the model cestode parasite

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