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Cell. 2014 Nov 20;159(5):1168-1187. doi: 10.1016/j.cell.2014.10.044.

Unraveling the biology of a fungal meningitis pathogen using chemical genetics.

Author information

1
Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94158, USA.
2
Department of Computer Science and Engineering, University of Minnesota, Minneapolis, MN 55455, USA.
3
Department of Chemistry, University of Rochester Medical Center, Rochester, NY 14643, USA.
4
Department of Clinical Microbiology and Infection Diseases, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel.
5
Department of Chemistry, University of Rochester Medical Center, Rochester, NY 14643, USA; Departments of Pediatrics and Microbiology/Immunology, University of Rochester School of Medicine and Dentistry, Rochester, NY 14643, USA.
6
Department of Computer Science and Engineering, University of Minnesota, Minneapolis, MN 55455, USA. Electronic address: cmyers@cs.umn.edu.
7
Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94158, USA. Electronic address: hitenmadhani@gmail.com.

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.

PMID:
25416953
PMCID:
PMC4243055
DOI:
10.1016/j.cell.2014.10.044
[Indexed for MEDLINE]
Free PMC Article

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