Journal article
Unraveling the biology of a fungal meningitis pathogen using chemical genetics
Cell, Vol.159(5), pp.1168-1187
11/20/2014
DOI: 10.1016/j.cell.2014.10.044
PMCID: PMC4243055
PMID: 25416953
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.
Details
- Title: Subtitle
- Unraveling the biology of a fungal meningitis pathogen using chemical genetics
- Creators
- Jessica C S Brown - Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94158, USAJustin Nelson - Department of Computer Science and Engineering, University of Minnesota, Minneapolis, MN 55455, USABenjamin VanderSluis - Department of Computer Science and Engineering, University of Minnesota, Minneapolis, MN 55455, USARaamesh Deshpande - Department of Computer Science and Engineering, University of Minnesota, Minneapolis, MN 55455, USAArielle Butts - Department of Chemistry, University of Rochester Medical Center, Rochester, NY 14643, USASarah Kagan - Department of Clinical Microbiology and Infection Diseases, Hadassah-Hebrew University Medical Center, Jerusalem 91120, IsraelItzhack Polacheck - Department of Clinical Microbiology and Infection Diseases, Hadassah-Hebrew University Medical Center, Jerusalem 91120, IsraelDamian J Krysan - 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, USAChad L Myers - Department of Computer Science and Engineering, University of Minnesota, Minneapolis, MN 55455, USA. Electronic address: cmyers@cs.umn.eduHiten D Madhani - Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94158, USA. Electronic address: hitenmadhani@gmail.com
- Resource Type
- Journal article
- Publication Details
- Cell, Vol.159(5), pp.1168-1187
- DOI
- 10.1016/j.cell.2014.10.044
- PMID
- 25416953
- PMCID
- PMC4243055
- ISSN
- 0092-8674
- eISSN
- 1097-4172
- Grant note
- R01 AI099206 / NIAID NIH HHS 1R01GM04975 / NIGMS NIH HHS R01 HG005084 / NHGRI NIH HHS 5R01AI099206 / NIAID NIH HHS T32 AI060537 / NIAID NIH HHS 1R01AI091422 / NIAID NIH HHS R01 AI100272 / NIAID NIH HHS 1R01HG005084 / NHGRI NIH HHS R01 AI096869 / NIAID NIH HHS R01 AI091422 / NIAID NIH HHS R01 GM104975 / NIGMS NIH HHS
- Language
- English
- Date published
- 11/20/2014
- Academic Unit
- Microbiology and Immunology; Stead Family Department of Pediatrics; Infectious Disease (Pediatrics)
- Record Identifier
- 9984093223802771
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