Browsing by Subject "Antiparasitic agents"

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    Characterization of Plasmodium Atg3-Atg8 Interaction Inhibitors Identifies Novel Alternative Mechanisms of Action in Toxoplasma gondii
    (American Society for Microbiology, 2018-01-25) Varberg, Joseph M.; LaFavers, Kaice A.; Arrizabalaga, Gustavo; Sullivan, William J., Jr.; Pharmacology and Toxicology, School of Medicine
    Protozoan parasites, including the apicomplexan pathogens Plasmodium falciparum (which causes malaria) and Toxoplasma gondii (which causes toxoplasmosis), infect millions of people worldwide and represent major human disease burdens. Despite their prevalence, therapeutic strategies to treat infections caused by these parasites remain limited and are threatened by the emergence of drug resistance, highlighting the need for the identification of novel drug targets. Recently, homologues of the core autophagy proteins, including Atg8 and Atg3, were identified in many protozoan parasites. Importantly, components of the Atg8 conjugation system that facilitate the lipidation of Atg8 are required for both canonical and parasite-specific functions and are essential for parasite viability. Structural characterization of the P. falciparum Atg3-Atg8 (PfAtg3-Atg8) interaction has led to the identification of compounds that block this interaction. Additionally, many of these compounds inhibit P. falciparum growth in vitro, demonstrating the viability of this pathway as a drug target. Given the essential role of the Atg8 lipidation pathway in Toxoplasma, we sought to determine whether three PfAtg3-Atg8 interaction inhibitors identified in the Medicines for Malaria Venture Malaria Box exerted a similar inhibitory effect in Toxoplasma While all three inhibitors blocked Toxoplasma replication in vitro at submicromolar concentrations, they did not inhibit T. gondii Atg8 (TgAtg8) lipidation. Rather, high concentrations of two of these compounds induced TgAtg8 lipidation and fragmentation of the parasite mitochondrion, similar to the effects seen following starvation and monensin-induced autophagy. Additionally, we report that one of the PfAtg3-Atg8 interaction inhibitors induces Toxoplasma egress and provide evidence that this is mediated by an increase in intracellular calcium in response to drug treatment.
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    Oral Administration of Clinically Relevant Antimalarial Drugs Does Not Modify the Murine Gut Microbiota
    (Springer Nature, 2019-08-16) Denny, Joshua E.; Schmidt, Nathan W.; Microbiology and Immunology, School of Medicine
    Malaria is an infectious disease responsible for the death of around 450,000 people annually. As an effective vaccine against the parasite that causes malaria is not available, antimalarial drug treatments are critical in fighting the disease. Previous data has shown that the gut microbiota is important in modulating the severity of malaria. Although it is well appreciated that antibiotics substantially alter the gut microbiota, it is largely unknown how antimalarial drugs impact the gut microbiota. We show here that the two commonly used artemisinin combination therapies of artesunate plus amodiaquine and artemether plus lumefantrine do not change the gut microbiota. The overall relative species abundance and alpha diversity remained stable after treatment, while beta diversity analysis showed minimal changes due to drug treatment, which were transient and quickly returned to baseline. Additionally, treatment with antimalarial drugs did not change the kinetics of later Plasmodium infection. Taken together, antimalarial drug administration does not affect the gut microbiota.