Therapeutic vulnerabilities of the drug-resistant fungal meningitis pathogen Cryptococcus neoformans

CRISPR-insert genome-wide screening in Cryptococcus neoformans predicts 1,297 essential genes, yet shows FKS1 is not essential despite echinocandin resistance.

• Why it matters: Limited therapies for drug-resistant fungal meningitis create a need to systematically identify drug targets and combination vulnerabilities in Cryptococcus neoformans.
• What they did: The authors used CRISPR-insert for scalable gene inactivation, then combined genome-wide screens with machine learning to predict essentiality (1,297 genes under liberal criteria). They experimentally tested essentiality for genes lacking human orthologs and mapped quantitative genetic interactions genome-wide.
• The result: Targeted deletion indicates FKS1 is not essential, and solid-state NMR shows fks1 mutants lack β-1,3-glucan, arguing against compensation by another synthase; interaction mapping reveals synthetic lethal dependencies of echinocandin resistance determinants, including calcineurin and Cdc50-Apt1 pathways.

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