Abstract
Prevalence studies revealed that one-third of the human population is chronically infected with Toxoplasma gondii. Presently, such infections are without medical treatment that effectively eradicates the parasite once it is in its latent form. Moreover, the therapeutics used to treat acute infections are poorly tolerated by patients and also cause the parasite to convert into long-lasting tissue cysts. Hence, there is a dire need for compounds with antiparasitic activity against all forms of T. gondii. This study examines the antiparasitic capacity of nine novel bisphenol Z (BPZ) derivatives to determine whether they possessed any activity that prevented T. gondii replication. To begin assessing the efficacy of the novel derivatives, parasites were treated with increasing concentrations of the compounds, then doubling assays and MitoTracker staining were performed. Three of the nine compounds demonstrated strong inhibitory activity, i.e., parasite replication significantly decreased with higher concentrations. Additionally, many of the treated parasites exhibited decreases in fluorescent signaling and disruption of mitochondrial morphology. These findings suggest that bisphenol Z compounds disrupt mitochondrial function to inhibit parasite replication and may provide a foundation for the development of new and effective treatment modalities against T. gondii.
Highlights
Toxoplasma gondii is a ubiquitous pathogen known for its remarkable capacity to infect nearly any nucleated cell in both animals and humans, and thereby cause significant disease, especially in immunocompromised individuals [1,2]
Infections in humans occur through a myriad of transmission routes, including congenitally [12], ingestion of water/food contaminated with infectious oocysts [13], consumption of undercooked meat from animals infected with latent bradyzoite tissue cysts [14,15], as well as through tissue transplantation [16,17]
Despite the fact that acute infections are generally self-limited and controlled by an intact immune system, the problem arises when the parasite escapes the immune response to develop into a dormant bradyzoite tissue cyst, allowing T. gondii to reside within the host for life
Summary
Toxoplasma gondii is a ubiquitous pathogen known for its remarkable capacity to infect nearly any nucleated cell in both animals and humans, and thereby cause significant disease, especially in immunocompromised individuals [1,2]. Asexual reproduction happens in a broad range of hosts and involves two major parasite forms: tachyzoites, the tissue destructive form that rapidly divides; and bradyzoites, a latent form that persists in the host for life [9,10,11]. Infections in humans occur through a myriad of transmission routes, including congenitally [12], ingestion of water/food contaminated with infectious oocysts [13], consumption of undercooked meat from animals infected with latent bradyzoite tissue cysts [14,15], as well as through tissue transplantation [16,17]. Despite the fact that acute infections are generally self-limited and controlled by an intact immune system, the problem arises when the parasite escapes the immune response to develop into a dormant bradyzoite tissue cyst, allowing T. gondii to reside within the host for life. Our results indicate that BPZ derivatives possess the capacity to significantly inhibit intracellular parasite replication, and that this antiparasitic activity may rely on the disruption of mitochondrial functionality and biogenesis, thereby laying the groundwork for further investigations
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