Metacytofilin Is a Potent Therapeutic Drug Candidate for Toxoplasmosis

Abstract

Background Toxoplasmosis, a parasitic disease caused by Toxoplasma gondii, is an important cause of miscarriage or adverse fetal effects, including neurological and ocular manifestations in humans. Current anti-Toxoplasma drugs have limited efficacy against toxoplasmosis and also have severe side effects. Therefore, novel efficacious drugs are urgently needed. Here, we identified metacytofilin (MCF) from a fungal Metarhizium species as a potential anti-Toxoplasma compound. Methods Anti-Toxoplasma activities of MCF and its derivatives were evaluated in vitro and in vivo using nonpregnant and pregnant mice. To understand the mode of action of MCF, the RNA expression of host and parasite genes was investigated by RNAseq. Results In vitro, MCF inhibited the viability of intracellular and extracellular T. gondii. Administering MCF intraperitoneally or orally to mice after infection with T. gondii tachyzoites increased mouse survival compared with the untreated animals. Remarkably, oral administration of MCF to pregnant mice prevented vertical transmission of the parasite. Interestingly, RNA sequencing of T. gondii–infected cells treated with MCF showed that MCF inhibited DNA replication and enhanced RNA degradation in the parasites. Conclusions With its potent anti–T. gondii activity, MCF is a strong candidate for future drug development against toxoplasmosis.

Urolithin-A attenuates neurotoxoplasmosis and alters innate response towards predator odor

“…Several targets have been proposed to underlie the anti- T. gondii activity of plant-derived natural products. These include interference of the parasite DNA synthesis, RNA degradation, mitochondrial function, lipid metabolism, glyoxalase pathway, calcium homeostasis, cytoskeleton integrity, and locomotion ( Doggett et al., 2012 ; Nagamune et al., 2007 ; De Pablos et al., 2010 ; Goo et al., 2015 ; Alday et al., 2017 ; Si et al., 2018 ; McConnell et al., 2018 ; Luan et al., 2019 ; Leesombun et al., 2020 ; Deng et al., 2020 ). Pro-oxidant effect to induce oxidative stress and DNA damage in the parasite has also been suggested ( Gopalakrishnan and Kumar, 2015 ; Adeyemi et al., 2020 ).…”

Antimalarial Agents as Therapeutic Tools Against Toxoplasmosis—A Short Bridge between Two Distant Illnesses

“…Cyclic depsipetides are part of a group enriched with many therapeutic properties, including antimicrobial, antioxidant, and immunomodulatory and are also inhibitory of several biomolecules and biomolecular processes, such as the activity of α-glucosidase, cholesterol acyltransferase, xanthine oxidase, and platelet aggregation [111]. Promising antiprotozoal activities were also observed for compounds belonging to this class, both against malaria and toxoplasmosis [110,112]. A library of compounds isolated from the beauvericin-like family of the cyclic depsipeptides exhibited activity against Plasmodium falciparum within the IC50% range 0.24-3.4 μg/mL [110].…”

“…This compound showed favorable results regarding its activity against T. gondii parasites. Analogously to AMPs, metacytofilin acts through a dual mechanism, targeting both the parasite directly through inhibition of its replicative cycle and the host immune system through suppression of the inflammatory processes and stimulation of immune cells to combat the infection [112]. A detailed mechanism of action of this compound can be seen in Scheme 2.…”

“…suppression of the inflammatory processes and stimulation of immune cells to combat the infection [112]. A detailed mechanism of action of this compound can be seen in Scheme 2.…”

“…The most common strains affecting humans, namely immunosuppressed patients and those with congenital toxoplasmosis, are types I and II [12]. Metacytofilin was shown to inhibit the intracellular growth of both type I and type II strains [112]. Additional advantageous properties of metacytofilin include a favorable pharmacokinetic profile, i.e., good gastrointestinal absorption, allowing for oral administration, which in turn translates into low production and storage costs, as well as privileged properties for distribution and administration.…”