Unraveling the Biology of a Fungal Meningitis Pathogen Using Chemical Genetics

被引：67

作者：

Brown, Jessica C. S. ^{[1
]}

Nelson, Justin ^{[2
]}

VanderSluis, Benjamin ^{[2
]}

Deshpande, Raamesh ^{[2
]}

Butts, Arielle ^{[3
]}

Kagan, Sarah ^{[4
]}

Polacheck, Itzhack ^{[4
]}

Krysan, Damian J. ^{[3
,5
,6
]}

Myers, Chad L. ^{[2
]}

Madhani, Hiten D. ^{[1
]}

机构：

[1] Univ Calif San Francisco, Dept Biochem & Biophys, San Francisco, CA 94158 USA

[2] Univ Minnesota, Dept Comp Sci & Engn, Minneapolis, MN 55455 USA

[3] Univ Rochester, Med Ctr, Dept Chem, Rochester, NY 14643 USA

[4] Hadassah Hebrew Univ, Med Ctr, Dept Clin Microbiol & Infect Dis, IL-91120 Jerusalem, Israel

[5] Univ Rochester, Sch Med & Dent, Dept Pediat, Rochester, NY 14643 USA

[6] Univ Rochester, Sch Med & Dent, Dept Microbiol Immunol, Rochester, NY 14643 USA

来源：

CELL | 2014年 / 159卷 / 05期

关键词：

BIOACTIVE COMPOUNDS; DRUG-COMBINATIONS; ANTIFUNGAL AGENTS; CAPSULE; MECHANISMS; RESISTANCE; VIRULENCE; YEAST; POLYSACCHARIDE; INHIBITOR;

D O I：

10.1016/j.cell.2014.10.044

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：1168 / 1187

页数：20

共 63 条

[41] Synergistic drug combinations tend to improve therapeutically relevant selectivity [J].

Lehar, Joseph ;

Krueger, Andrew S. ;

Avery, William ;

Heilbut, Adrian M. ;

Johansen, Lisa M. ;

Price, E. Roydon ;

Rickles, Richard J. ;

Short, Glenn F., III ;

Staunton, Jane E. ;

Jin, Xiaowei ;

Lee, Margaret S. ;

Zimmermann, Grant R. ;

Borisy, Alexis A. .

NATURE BIOTECHNOLOGY, 2009, 27 (07) :659-U116

[42] Proteasome inhibition in wild-type yeast Saccharomyces cerevisiae cells [J].

Liu, Chang ;

Apodaca, Jennifer ;

Davis, Laura E. ;

Rao, Hai .

BIOTECHNIQUES, 2007, 42 (02) :156-+

[43] Systematic genetic analysis of virulence in the human fungal pathogen Cryptococcus neoformans [J].

Liu, Oliver W. ;

Chun, Cheryl D. ;

Chow, Eric D. ;

Chen, Changbin ;

Madhani, Hiten D. ;

Noble, Suzanne M. .

CELL, 2008, 135 (01) :174-188

[44] Parallel β-helix proteins required for accurate capsule polysaccharide synthesis and virulence in the yeast Cryptococcus neoformans [J].

Liu, Oliver W. ;

Kelly, Mark J. S. ;

Chow, Eric D. ;

Madhani, Hiten D. .

EUKARYOTIC CELL, 2007, 6 (04) :630-640

[45] Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010 [J].

Lozano, Rafael ;

Naghavi, Mohsen ;

Foreman, Kyle ;

Lim, Stephen ;

Shibuya, Kenji ;

Aboyans, Victor ;

Abraham, Jerry ;

Adair, Timothy ;

Aggarwal, Rakesh ;

Ahn, Stephanie Y. ;

Alvarado, Miriam ;

Anderson, H. Ross ;

Anderson, Laurie M. ;

Andrews, Kathryn G. ;

Atkinson, Charles ;

Baddour, Larry M. ;

Barker-Collo, Suzanne ;

Bartels, David H. ;

Bell, Michelle L. ;

Benjamin, Emelia J. ;

Bennett, Derrick ;

Bhalla, Kavi ;

Bikbov, Boris ;

Bin Abdulhak, Aref ;

Birbeck, Gretchen ;

Blyth, Fiona ;

Bolliger, Ian ;

Boufous, Soufi Ane ;

Bucello, Chiara ;

Burch, Michael ;

Burney, Peter ;

Carapetis, Jonathan ;

Chen, Honglei ;

Chou, David ;

Chugh, Sumeet S. ;

Coffeng, Luc E. ;

Colan, Steven D. ;

Colquhoun, Samantha ;

Colson, K. Ellicott ;

Condon, John ;

Connor, Myles D. ;

Cooper, Leslie T. ;

Corriere, Matthew ;

Cortinovis, Monica ;

de Vaccaro, Karen Courville ;

Couser, William ;

Cowie, Benjamin C. ;

Criqui, Michael H. ;

Cross, Marita ;

Dabhadkar, Kaustubh C. .

LANCET, 2012, 380 (9859) :2095-2128

[46]

Mandell G.L., 2010, MANDELL DOUGLAS BENN, V7th, DOI DOI 10.1086/655696

[47] Defining Fractional Inhibitory Concentration Index Cutoffs for Additive Interactions Based on Self-Drug Additive Combinations, Monte Carlo Simulation Analysis, and In Vitro-In Vivo Correlation Data for Antifungal Drug Combinations against Aspergillus fumigatus [J].

Meletiadis, Joseph ;

Pournaras, Spyros ;

Roilides, Emmanuel ;

Walsh, Thomas J. .

ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 2010, 54 (02) :602-609

[48]

Morgan D.O., 2007, The Cell Cycle: Principles of Control

[49] Phenotypic Landscape of a Bacterial Cell [J].

Nichols, Robert J. ;

Sen, Saunak ;

Choo, Yoe Jin ;

Beltrao, Pedro ;

Zietek, Matylda ;

Chaba, Rachna ;

Lee, Sueyoung ;

Kazmierczak, Krystyna M. ;

Lee, Karis J. ;

Wong, Angela ;

Shales, Michael ;

Lovett, Susan ;

Winkler, Malcolm E. ;

Krogan, Nevan J. ;

Typas, Athanasios ;

Gross, Carol A. .

CELL, 2011, 144 (01) :143-156

[50] The Cryptococcus neoformans Capsule: a Sword and a Shield [J].

O'Meara, Teresa R. ;

Alspaugh, J. Andrew .

CLINICAL MICROBIOLOGY REVIEWS, 2012, 25 (03) :387-408

← 1 2 3 4 5 6 7 →