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PLoS Pathog ; 20(4): e1011906, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38669269

RESUMO

The apicomplexan parasite Cryptosporidium is a leading cause of childhood diarrhea in developing countries. Current treatment options are inadequate and multiple preclinical compounds are being actively pursued as potential drugs for cryptosporidiosis. Unlike most apicomplexans, Cryptosporidium spp. sequentially replicate asexually and then sexually within a single host to complete their lifecycles. Anti-cryptosporidial compounds are generally identified or tested through in vitro phenotypic assays that only assess the asexual stages. Therefore, compounds that specifically target the sexual stages remain unexplored. In this study, we leveraged the ReFRAME drug repurposing library against a newly devised multi-readout imaging assay to identify small-molecule compounds that modulate macrogamont differentiation and maturation. RNA-seq studies confirmed selective modulation of macrogamont differentiation for 10 identified compounds (9 inhibitors and 1 accelerator). The collective transcriptomic profiles of these compounds indicates that translational repression accompanies Cryptosporidium sexual differentiation, which we validated experimentally. Additionally, cross comparison of the RNA-seq data with promoter sequence analysis for stage-specific genes converged on a key role for an Apetala 2 (AP2) transcription factor (cgd2_3490) in differentiation into macrogamonts. Finally, drug annotation for the ReFRAME hits indicates that an elevated supply of energy equivalence in the host cell is critical for macrogamont formation.


Assuntos
Criptosporidiose , Cryptosporidium , Estágios do Ciclo de Vida , Proteínas de Protozoários , Criptosporidiose/parasitologia , Criptosporidiose/tratamento farmacológico , Proteínas de Protozoários/metabolismo , Proteínas de Protozoários/genética , Estágios do Ciclo de Vida/efeitos dos fármacos , Cryptosporidium/efeitos dos fármacos , Cryptosporidium/genética , Cryptosporidium/metabolismo , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Animais , Humanos , Bibliotecas de Moléculas Pequenas/farmacologia
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