New hit compounds against Trypanosoma cruzi derived from mining yeast chemogenomic profiling data

Chagas disease, caused by Trypanosoma cruzi, remains a major neglected tropical disease with limited therapeutic options. To accelerate drug discovery, we developed a bioinformatic and chemoinformatic pipeline that integrates chemogenomic profiling data from Saccharomyces cerevisiae with orthology and essentiality information from trypanosomatids. First, we integrated data from five reference yeast chemogenomic screens that assayed a total of 2,788 compounds against a collection of 5,811 gene-deletion strains, thus providing a rich matrix of ∼270,000 gene-drug associations. Using these data as input, the pipeline filtered and prioritized 193 candidate bioactive compounds with links to conserved parasite orthologs. Following manual curation, 22 compounds were selected for experimental evaluation. In vitro assays against intracellular T. cruzi revealed two novel hits with micromolar EC[Formula: see text] values and favorable selectivity indices. This work demonstrates that comparative chemogenomics can be leveraged for drug repositioning in parasitic protozoa, providing a tractable strategy to enrich lead-like compounds, and expand the chemical space available for Chagas disease drug discovery. Importantly, both the curated yeast chemogenomic data set and the analysis pipeline are reusable resources, and the prioritized compound list offers a ready-to-test chemical space that can be further explored, validated, and expanded by other researchers and for additional organisms.