TY - JOUR
T1 - Unraveling the biology of a fungal meningitis pathogen using chemical genetics
AU - Brown, Jessica C.S.
AU - Nelson, Justin
AU - Vandersluis, Benjamin
AU - Deshpande, Raamesh
AU - Butts, Arielle
AU - Kagan, Sarah
AU - Polacheck, Itzhack
AU - Krysan, Damian J.
AU - Myers, Chad L.
AU - Madhani, Hiten D.
N1 - Publisher Copyright:
© 2014 Elsevier Inc. All rights reserved.
PY - 2014/11/20
Y1 - 2014/11/20
N2 - 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.
AB - 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.
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U2 - 10.1016/j.cell.2014.10.044
DO - 10.1016/j.cell.2014.10.044
M3 - Article
C2 - 25416953
AN - SCOPUS:84911498408
SN - 0092-8674
VL - 159
SP - 1168
EP - 1187
JO - Cell
JF - Cell
IS - 5
ER -
