Metacytofilin Is a Potent Therapeutic Drug Candidate for Toxoplasmosis

• Published in: The Journal of infectious diseases Vol. 221; no. 5; pp. 766 - 774
• Main Authors: Leesombun, Arpron, Iijima, Masatomi, Umeda, Kousuke, Kondoh, Daisuke, Pagmadulam, Baldorj, Abdou, Ahmed M, Suzuki, Yutaka, Ohba, Shun-Ichi, Isshiki, Kunio, Kimura, Tomoyuki, Kubota, Yumiko, Sawa, Ryuichi, Nihei, Coh-Ichi, Nishikawa, Yoshifumi
• Format: Journal Article
• Language: English
• Published: US Oxford University Press 18-02-2020
• Subjects: Biodegradation; DNA biosynthesis; Drug development; Fetuses; Oral administration; Parasitic diseases; Pregnancy; Protozoa; Ribonucleic acid; RNA; Tachyzoites; Toxoplasma; Toxoplasmosis; congenital toxoplasmosis; drug; Metarhizium; Toxoplasma gondii
• ISSN: 0022-1899; 1537-6613
• DOI: 10.1093/infdis/jiz501

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.
Metacytofilin possesses a cidal effect against Toxoplasma gondii by inhibiting DNA replication and enhancing RNA degradation in the parasites. Oral administration of experimental mice with metacytofilin controlled toxoplasmosis. Metacytofilin is a strong candidate for future drug development against toxoplasmosis.