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Altiratinib blocks Toxoplasma gondii and Plasmodium falciparum development by selectively targeting a kinase critical for splicing

ABSTRACT: Purpose: To shed light on the parasiticidal mechanisms of Altiratinib, we have adapted a workflow which combines a forward genetic approach based on transcriptome sequencing, computational mutation discovery and CRISPR/Cas9 genome editing in Toxoplasma gondii. Drug-resistant parasites were generated by chemical random mutagenesis. Multiple independent resistant lines were isolated. Single nucleotide variations (SNVs) were identified based on NGS transcriptomic analysis. By focusing on mutations present in coding sequences, we identified a single gene, TgPRP4K, that harbored SNVs leading to amino acid substitutions in 5 out of the 6 drug-resistant lines that were not present in the parental strain. Finally, using CRISPR/Cas9 genome editing we confirmed that the mutations identified confer resistance against Altiratinib.

ORGANISM(S): Toxoplasma gondii RH

PROVIDER: GSE193614 | GEO | 2022/03/30

REPOSITORIES: GEO

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