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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.



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