Medicines for malaria venture pandemic box in vitro screening identifies compounds highly active against the tachyzoite stage of 'Toxoplasma Gondii'

• Published in: Tropical medicine and infectious disease 2023-11, Vol.8 (12), p.1-16
• Main Authors: Dos Santos, Mike, Oliveira Costa, Andréia Luiza, Vaz, Guilherme Henrique de Souza, de Souza, Gabriela Carolina Alves, Vitor, Ricardo Wagner de Almeida, Martins-Duarte, Érica S
• Format: Article
• Language: English
• Subjects: Cytotoxicity; Diagnosis; drug repositioning; Drugs; Evaluation; Immune system; Immunofluorescence; Infectious diseases; Malaria; Methodology; new therapies; Pandemics; Parasites; Parasitic diseases; Pathogens; Pharmaceutical industry; Protozoa; Toxoplasmosis; Transmission electron microscopy; treatment; ultrastructure; Womens health
• ISSN: 2414-6366; 2414-6366
• DOI: 10.3390/tropicalmed8120510

Toxoplasmosis is a disease that causes high mortality in immunocompromised individuals, such as AIDS patients, and sequelae in congenitally infected newborns. Despite its great medical importance, there are few treatments available and these are associated with adverse events and resistance. In this work, after screening the drugs present in the Medicines for Malaria Venture Pandemic Box, we found new hits with anti-Toxoplasma gondii activity. Through our analysis, we selected twenty-three drugs or drug-like compounds that inhibited the proliferation of T. gondii tachyzoites in vitro by more than 50% at a concentration of 1 muM after seven days of treatment. Nineteen of these compounds have never been reported active before against T. gondii. Inhibitory curves showed that most of these drugs were able to inhibit parasite replication with IC50 values on the nanomolar scale. To better understand the unprecedented effect of seven compounds against T. gondii tachyzoites, an ultrastructural analysis was carried out using transmission electron mi- croscopy. Treatment with 0.25 muM verdinexor, 3 nM MMV1580844, and 0.25 muM MMV019724 induced extensive vacuolization, complete ultrastructural disorganization, and lytic effects in the parasite, respectively, and all of them showed alterations in the division process. Treatment with 1 muM Eberconazole, 0.5 muM MMV1593541, 1 muM MMV642550, 1 muM RWJ-67657, and 1 muM URMC-099-C also caused extensive vacuolization in the parasite. The activity of these drugs against intracellular tachyzoites supports the idea that the drugs selected in the Pandemic Box could be potential future drugs for the treatment of acute toxoplasmosis.