Unraveling the biology of a fungal meningitis pathogen using chemical genetics

Jessica C.S. Brown, Justin Nelson, Benjamin Vandersluis, Raamesh Deshpande, Arielle Butts, Sarah Kagan, Itzhack Polacheck, Damian J. Krysan, Chad L. Myers, Hiten D. Madhani

Research output: Contribution to journalArticlepeer-review

40 Scopus citations

Abstract

The fungal meningitis pathogen Cryptococcus neoformans is a central driver of mortality in HIV/AIDS. We report a genome-scale chemical genetic data map for this pathogen that quantifies the impact of 439 small-molecule challenges on 1,448 gene knockouts. We identified chemical phenotypes for 83% of mutants screened and at least one genetic response for each compound. C. neoformans chemical-genetic responses are largely distinct from orthologous published profiles of Saccharomyces cerevisiae, demonstrating the importance of pathogen-centered studies. We used the chemical-genetic matrix to predict novel pathogenicity genes, infer compound mode of action, and to develop an algorithm, O2M, that predicts antifungal synergies. These predictions were experimentally validated, thereby identifying virulence genes, a molecule that triggers G2/M arrest and inhibits the Cdc25 phosphatase, and many compounds that synergize with the antifungal drug fluconazole. Our work establishes a chemical-genetic foundation for approaching an infection responsible for greater than one-third of AIDS-related deaths. PaperClip

Original languageEnglish (US)
Pages (from-to)1168-1187
Number of pages20
JournalCell
Volume159
Issue number5
DOIs
StatePublished - Nov 20 2014

Bibliographical note

Funding Information:
This work was supported by NIH grants 5R01AI099206 to H.D.M., 1R01AI091422 to D.J.K., 1R01HG005084 and 1R01GM04975 to C.L.M, and a grant from the CIFAR Genetic Networks Program to C.L.M.

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