This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Supplemental material
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Liu, M.
Right arrow Articles by Wang, Y.-K.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Liu, M.
Right arrow Articles by Wang, Y.-K.

 Previous Article  |  Next Article 

Eukaryotic Cell, April 2006, p. 638-649, Vol. 5, No. 4
1535-9778/06/$08.00+0     doi:10.1128/EC.5.4.638-649.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Conserved Fungal Genes as Potential Targets for Broad-Spectrum Antifungal Drug Discovery{dagger}

Mengping Liu,1 Matthew D. Healy,2 Brian A. Dougherty,2 Kim M. Esposito,3 Trina C. Maurice,1 Charles E. Mazzucco,1 Robert E. Bruccoleri,2 Daniel B. Davison,2 Marybeth Frosco,1 John F. Barrett,1 and Ying-Kai Wang1*

Departments of Infectious Diseases,1 Applied Genomics,2 Lead Discovery, Bristol-Myers Squibb Company Pharmaceutical Research Institute, 5 Research Parkway, Wallingford, Connecticut 064923

Received 2 December 2005/ Accepted 26 January 2006

The discovery of novel classes of antifungal drugs depends to a certain extent on the identification of new, unexplored targets that are essential for growth of fungal pathogens. Likewise, the broad-spectrum capacity of future antifungals requires the target gene(s) to be conserved among key fungal pathogens. Using a genome comparison (or concordance) tool, we identified 240 conserved genes as candidates for potential antifungal targets in 10 fungal genomes. To facilitate the identification of essential genes in Candida albicans, we developed a repressible C. albicans MET3 (CaMET3) promoter system capable of evaluating gene essentiality on a genome-wide scale. The CaMET3 promoter was found to be highly amenable to controlled gene expression, a prerequisite for use in target-based whole-cell screening. When the expression of the known antifungal target C. albicans ERG1 was reduced via down-regulation of the CaMET3 promoter, the CaERG1 conditional mutant strain became hypersensitive, specifically to its inhibitor, terbinafine. Furthermore, parallel screening against a small compound library using the CaERG1 conditional mutant under normal and repressed conditions uncovered several hypersensitive compound hits. This work therefore demonstrates a streamlined process for proceeding from selection and validation of candidate antifungal targets to screening for specific inhibitors.

* Corresponding author. Mailing address: Bristol-Myers Squibb Company Pharmaceutical Research Institute, 5 Research Parkway, Wallingford, CT 06492. Phone: (203) 677-7015. Fax: (203) 677-6771. E-mail: ying-kai.wang{at}bms.com.

{dagger} Supplemental material for this article may be found at http://ec.asm.org/.

Eukaryotic Cell, April 2006, p. 638-649, Vol. 5, No. 4
1535-9778/06/$08.00+0     doi:10.1128/EC.5.4.638-649.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Chauhan, N., Calderone, R. (2008). Two-Component Signal Transduction Proteins as Potential Drug Targets in Medically Important Fungi. Infect. Immun. 76: 4795-4803 [Full Text]  
  • Monk, B. C., Goffeau, A. (2008). Outwitting Multidrug Resistance to Antifungals. Science 321: 367-369 [Abstract] [Full Text]  
  • Rodaki, A., Young, T., Brown, A. J. P. (2006). Effects of Depleting the Essential Central Metabolic Enzyme Fructose-1,6-Bisphosphate Aldolase on the Growth and Viability of Candida albicans: Implications for Antifungal Drug Target Discovery.. Eukaryot Cell 5: 1371-1377 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»