Abstract
The currently available anti-Toxoplasma agents have serious limitations. This systematic review was performed to evaluate drugs and new compounds used for the treatment of toxoplasmosis. Data was systematically collected from published papers on the efficacy of drugs/compounds used against Toxoplasma gondii (T. gondii) globally during 2006–2016. The searched databases were PubMed, Google Scholar, Science Direct, ISI Web of Science, EBSCO, and Scopus. One hundred and eighteen papers were eligible for inclusion in this systematic review, which were both in vitro and in vivo studies. Within this review, 80 clinically available drugs and a large number of new compounds with more than 39 mechanisms of action were evaluated. Interestingly, many of the drugs/compounds evaluated against T. gondii act on the apicoplast. Therefore, the apicoplast represents as a potential drug target for new chemotherapy. Based on the current findings, 49 drugs/compounds demonstrated in vitro half-maximal inhibitory concentration (IC50) values of below 1 μM, but most of them were not evaluated further for in vivo effectiveness. However, the derivatives of the ciprofloxacin, endochin-like quinolones and 1-[4-(4-nitrophenoxy) phenyl] propane-1-one (NPPP) were significantly active against T. gondii tachyzoites both in vitro and in vivo. Thus, these compounds are promising candidates for future studies. Also, compound 32 (T. gondii calcium-dependent protein kinase 1 inhibitor), endochin-like quinolones, miltefosine, rolipram abolish, and guanabenz can be repurposed into an effective anti-parasitic with a unique ability to reduce brain tissue cysts (88.7, 88, 78, 74, and 69%, respectively). Additionally, no promising drugs are available for congenital toxoplasmosis. In conclusion, as current chemotherapy against toxoplasmosis is still not satisfactory, development of well-tolerated and safe specific immunoprophylaxis in relaxing the need of dependence on chemotherapeutics is a highly valuable goal for global disease control. However, with the increasing number of high-risk individuals, and absence of a proper vaccine, continued efforts are necessary for the development of novel treatment options against T. gondii. Some of the novel compounds reviewed here may represent good starting points for the discovery of effective new drugs. In further, bioinformatic and in silico studies are needed in order to identify new potential toxoplasmicidal drugs.
Highlights
Toxoplasma gondii (T. gondii), an obligate intracellular, parasitic protozoan, is the etiologic agent of toxoplasmosis
In the current systematic review, 80 clinically available drugs (Table 1) and several new compounds with more than 39 pathways/ mechanisms of action were evaluated against T. gondii in both in vitro and in vivo studies
Several target based drug screens were identified against T. gondii include mitochondrial electron transport chain, calcium-dependent protein kinase 1, type II fatty acid synthesis, DNA synthesis, DNA
Summary
Toxoplasma gondii (T. gondii), an obligate intracellular, parasitic protozoan, is the etiologic agent of toxoplasmosis. About 30– 50% of the world population is infected with the parasite, and it is the most prevalent infection among humans (Tenter et al, 2000; Flegr et al, 2014). In the United States, the Centers for Disease Control and Prevention (CDC) reported that 22.5% of the population 12 years and older have been infected with Toxoplasma with 1.1 million new infections each year, making it the second most common cause of deaths due to foodborne diseases (an estimated 327 deaths) and the fourth leading cause of hospitalizations attributable to foodborne illness (an estimated 4428 hospitalizations). An estimated 400–4000 infants are born with congenital toxoplasmosis in the United States each year (Jones et al, 2014)
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