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Medicines for Malaria Venture Pandemic Box In Vitro Screening Identifies Compounds Highly Active against the Tachyzoite Stage of Toxoplasma gondii

Authors :
Mike dos Santos
Andréia Luiza Oliveira Costa
Guilherme Henrique de Souza Vaz
Gabriela Carolina Alves de Souza
Ricardo Wagner de Almeida Vitor
Érica S. Martins-Duarte
Source :
Tropical Medicine and Infectious Disease, Vol 8, Iss 12, p 510 (2023)
Publication Year :
2023
Publisher :
MDPI AG, 2023.

Abstract

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 µM 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 microscopy. Treatment with 0.25 µM verdinexor, 3 nM MMV1580844, and 0.25 µM 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 µM Eberconazole, 0.5 µM MMV1593541, 1 µM MMV642550, 1 µM RWJ-67657, and 1 µM 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.

Details

Language :
English
ISSN :
24146366
Volume :
8
Issue :
12
Database :
Directory of Open Access Journals
Journal :
Tropical Medicine and Infectious Disease
Publication Type :
Academic Journal
Accession number :
edsdoj.b8763f9e48574117a62de36841fae328
Document Type :
article
Full Text :
https://doi.org/10.3390/tropicalmed8120510