Repurposing of the Malaria Box for Babesia microti in mice identifies novel active scaffolds against piroplasmosis

Autor:	Mohamed Abdo Rizk, Hanadi B. Baghdadi, Shimaa Abd El-Salam El-Sayed, Rasha Eltaysh, Ikuo Igarashi
Rok vydání:	2022
Předmět:	Imidocarb Mice Infectious Diseases Cysteine Proteases Babesiosis Theileria Drug Repositioning Animals Parasitology Babesia microti Clofazimine Atovaquone Malaria
Zdroj:	Parasitesvectors. 15(1)
ISSN:	1756-3305
Popis:	Background An innovative approach has been introduced for identifying and developing novel potent and safe anti-Babesia and anti-Theileria agents for the control of animal piroplasmosis. In the present study, we evaluated the inhibitory effects of Malaria Box (MBox) compounds (n = 8) against the growth of Babesia microti in mice and conducted bioinformatics analysis between the selected hits and the currently used antibabesial drugs, with far-reaching implications for potent combinations. Methods A fluorescence assay was used to evaluate the in vivo inhibitory effects of the selected compounds. Bioinformatics analysis was conducted using hierarchical clustering, distance matrix and molecular weight correlation, and PubChem fingerprint. The compounds with in vivo potential efficacy were selected to search for their target in the piroplasm parasites using quantitative PCR (qPCR). Results Screening the MBox against the in vivo growth of the B. microti parasite enabled the discovery of potent new antipiroplasm drugs, including MMV396693 and MMV665875. Interestingly, statistically significant (P Theileria equi in vitro culture in comparison with untreated cultures. MMV396693/clofazimine and MMV665875/atovaquone (AV) showed maximum structural similarity (MSS) with each other. The distance matrix results indicate promising antibabesial efficacy of combination therapies consisting of either MMV665875 and AV or MMV396693 and imidocarb dipropionate (ID). Conclusions Inhibitory and hematology assay results suggest that MMV396693 and MMV665875 are potent antipiroplasm monotherapies. The structural similarity results indicate that MMV665875 and MMV396693 have a similar mode of action as AV and ID, respectively. Our findings demonstrated that MBox compounds provide a promising lead for the development of new antibabesial therapeutic alternatives. Graphical Abstract
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::b8cef9c7a92a8bf2c3f4204dd908a1aa https://pubmed.ncbi.nlm.nih.gov/36123705 Zobrazit plný text záznamu Plný text ve formátu PDF Plný text ve formátu HTML
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