Clinically Available Medicines Demonstrating Anti-Toxoplasma Activity

Neville, Andrew J.; Zach, Sydney J.; Wang, Xiaofang; Larson, Joshua J.; Judge, Abigail K.; Davis, Lisa; Vennerstrom, Jonathan L.; Davis, Paul H.

doi:10.1128/aac.02009-15

Cited by 93 publications

(82 citation statements)

References 103 publications

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“…The search for new anti-Toxoplasma gondii drugs has been active for several decades [12,13], but only a few drugs are currently approved for use in humans [1,27]. Although sulfa drugs can be effectively used for the prevention and control of T. gondii infection in humans and animals, their side effects should not be ignored [28].…”

Section: Discussionmentioning

confidence: 99%

Transcriptional changes in Toxoplasma gondii in response to treatment with monensin

Zhai

Elsheikha

et al. 2020

Parasites Vectors

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Background: Infection with the apicomplexan protozoan parasite T. gondii can cause severe and potentially fatal cerebral and ocular disease, especially in immunocompromised individuals. The anticoccidial ionophore drug monensin has been shown to have anti-Toxoplasma gondii properties. However, the comprehensive molecular mechanisms that underlie the effect of monensin on T. gondii are still largely unknown. We hypothesized that analysis of T. gondii transcriptional changes induced by monensin treatment can reveal new aspects of the mechanism of action of monensin against T. gondii.Methods: Porcine kidney (PK)-15 cells were infected with tachyzoites of T. gondii RH strain. Three hours post-infection, PK-15 cells were treated with 0.1 μM monensin, while control cells were treated with medium only. PK-15 cells containing intracellular tachyzoites were harvested at 6 and 24 h post-treatment, and the transcriptomic profiles of T. gondii-infected PK-15 cells were examined using high-throughput RNA sequencing (RNA-seq). Quantitative real-time PCR was used to verify the expression of 15 differentially expressed genes (DEGs) identified by RNA-seq analysis.Results: A total of 4868 downregulated genes and three upregulated genes were identified in monensin-treated T. gondii, indicating that most of T. gondii genes were suppressed by monensin. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis of T. gondii DEGs showed that T. gondii metabolic and cellular pathways were significantly downregulated. Spliceosome, ribosome, and protein processing in endoplasmic reticulum were the top three most significantly enriched pathways out of the 30 highly enriched pathways detected in T. gondii. This result suggests that monensin, via down-regulation of protein biosynthesis in T. gondii, can limit the parasite growth and proliferation. Conclusions:Our findings provide a comprehensive insight into T. gondii genes and pathways with altered expression following monensin treatment. These data can be further explored to achieve better understanding of the specific mechanism of action of monensin against T. gondii.

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Section: Discussionmentioning

confidence: 99%

Transcriptional changes in Toxoplasma gondii in response to treatment with monensin

Zhai

Elsheikha

et al. 2020

Parasites Vectors

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“…In summary, there is a compelling need for safe and effective treatments for toxoplasmosis (7,8). A comprehensive analysis of the present stage of toxoplasmosis treatments has recently been published (5,9).…”

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confidence: 99%

Synergistic Activity between Statins and Bisphosphonates against Acute Experimental Toxoplasmosis

Szajnman

et al. 2017

Antimicrob Agents Chemother

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Bisphosphonates are widely used for the treatment of bone disorders. These drugs also inhibit the growth of a variety of protozoan parasites, such as Toxoplasma gondii, the etiologic agent of toxoplasmosis. The target of the most potent bisphosphonates is the isoprenoid biosynthesis pathway enzyme farnesyl diphosphate synthase (FPPS). Based on our previous work on the inhibitory effect of sulfurcontaining linear bisphosphonates against T. gondii, we investigated the potential synergistic interaction between one of these derivatives, 1-[(n-heptylthio)ethyl]-1,1-bisphosphonate (C7S), and statins, which are potent inhibitors of the host 3-hydroxy-3-methyl glutaryl-coenzyme A reductase (3-HMG-CoA reductase). C7S showed high activity against the T. gondii bifunctional farnesyl diphosphate (FPP)/geranylgeranyl diphosphate (GGPP) synthase (TgFPPS), which catalyzes the formation of FPP and GGPP (50% inhibitory concentration [IC 50 ] ϭ 31 Ϯ 0.01 nM [mean Ϯ standard deviation]), and modest effect against the human FPPS (IC 50 ϭ 1.3 Ϯ 0.5 M). We tested combinations of C7S with statins against the in vitro replication of T. gondii. We also treated mice infected with a lethal dose of T. gondii with similar combinations. We found strong synergistic activities when using low doses of C7S, which were stronger in vivo than when tested in vitro. We also investigated the synergism of several commercially available bisphosphonates with statins both in vitro and in vivo. Our results provide evidence that it is possible to develop drug combinations that act synergistically by inhibiting host and parasite enzymes in vitro and in vivo.

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“…Fluoroquinolones are the known DNA replication inhibitors that target prokaryotic type II topoisomerases (Collin et al, 2011). In two studies, researchers showed that derivatives of the antibiotic ciprofloxacin, a fluoroquinolone, are active against T. gondii tachyzoites both in vitro and in vivo (Neville et al, 2015). While all mice treated with ciprofloxacin died by day 10 post-infection, some mice treated with ciprofloxacin derivatives remained alive for at least 60 days, suggesting that ciprofloxacin derivatives cured T. gondii infection in treated mice (Dubar et al, 2011; Martins-Duarte et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

A Systematic Review of In vitro and In vivo Activities of Anti-Toxoplasma Drugs and Compounds (2006–2016)

et al. 2017

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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.

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Clinically Available Medicines Demonstrating Anti-Toxoplasma Activity

Cited by 93 publications

References 103 publications

Transcriptional changes in Toxoplasma gondii in response to treatment with monensin

Transcriptional changes in Toxoplasma gondii in response to treatment with monensin

Synergistic Activity between Statins and Bisphosphonates against Acute Experimental Toxoplasmosis

A Systematic Review of In vitro and In vivo Activities of Anti-Toxoplasma Drugs and Compounds (2006–2016)

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