Large-scale essential gene identification in Candida albicans and applications to antifungal drug discovery

被引:395
|
作者
Roemer, T [1 ]
Jiang, B
Davison, J
Ketela, T
Veillette, K
Breton, A
Tandia, F
Linteau, A
Sillaots, S
Marta, C
Martel, N
Veronneau, S
Lemieux, S
Kauffman, S
Becker, J
Storms, R
Boone, C
Bussey, H
机构
[1] Elitra Canada, Montreal, PQ H2X 3Y8, Canada
[2] Elitra Pharmaceut, San Diego, CA 92121 USA
[3] Univ Tennessee, Dept Microbiol, Knoxville, TN 37919 USA
[4] Concordia Univ, Dept Biol, Montreal, PQ H3G 1M8, Canada
[5] Univ Toronto, Banting & Best Dept Med Res, Toronto, ON M5G 1L6, Canada
[6] Univ Toronto, Dept Med Genet & Microbiol, Toronto, ON M5G 1L6, Canada
[7] McGill Univ, Dept Biol, Montreal, PQ H3A 1B1, Canada
关键词
D O I
10.1046/j.1365-2958.2003.03697.x
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
Candida albicans is the primary fungal pathogen of humans. Despite the need for novel drugs to combat fungal infections [Sobel, J. D. ( 2000) Clin Infectious Dis 30: 652], antifungal drug discovery is currently limited by both the availability of suitable drug targets and assays to screen corresponding targets. A functional genomics approach based on the diploid C. albicans genome sequence, termed GRACE(TM) (gene replacement and conditional expression), was used to assess gene essentiality through a combination of gene replacement and conditional gene expression. In a systematic application of this approach, we identify 567 essential genes in C. albicans. Interestingly, evaluating the conditional phenotype of all identifiable C. albicans homologues of the Saccharomyces cerevisiae essential gene set [Giaever, G., Chu, A. M., Ni, L., Connelly, C., Riles, L., Veronneau, S., et al. ( 2002) Nature 418: 387 - 391] by GRACE revealed only 61% to be essential in C. albicans, emphasizing the importance of performing such studies directly within the pathogen. Construction of this conditional mutant strain collection facilitates large-scale examination of terminal phenotypes of essential genes. This information enables preferred drug targets to be selected from the C. albicans essential gene set by phenotypic information derived both in vitro, such as cidal versus static terminal phenotypes, as well as in vivo through virulence studies using conditional strains in an animal model of infection. In addition, the combination of phenotypic and bioinformatic analyses further improves drug target selection from the C. albicans essential gene set, and their respective conditional mutant strains may be directly used as sensitive whole-cell assays for drug screening.
引用
收藏
页码:167 / 181
页数:15
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