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

被引:67
作者
Rodaki, Alexandra
Young, Tim
Brown, Alistair J. P. [1 ]
机构
[1] Univ Aberdeen, Aberdeen Fungal Grp, Sch Med Sci, Inst Med Sci, Aberdeen AB25 2ZD, Scotland
[2] Pfizer Ltd, Discovery Biol, Sandwich CT13 9NJ, Kent, England
基金
英国惠康基金;
关键词
D O I
10.1128/EC.00115-06
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
摘要
The central metabolic enzyme fructose-1,6-bisphosphate aldolase (Fba1p) catalyzes a reversible reaction required for both glycolysis and gluconeogenesis. Fba1p is a potential antifungal target because it is essential in yeast and because fungal and human aldolases differ significantly. To test the validity of Fba1p as an antifungal target, we have examined the effects of depleting this enzyme in the major fungal pathogen Candida albicans. Using a methionine/cysteine-conditional mutant (MET3-FBA1/fba1), we have shown that Fba1p is required for the growth of C albicans. However, Fba1p must be depleted to below 5% of wild-type levels before growth is blocked. Furthermore, Fba1p depletion exerts static rather than cidal effects upon C albicans. Fba1p is a relatively abundant and stable protein in C albicans, and hence, Fba1p levels decay relatively slowly following MET3-FBA1 shutoff. Taken together, our observations can account for our observation that the virulence of MET3-FBA1/fba1 cells is only partially attenuated in the mouse model of systemic candidiasis. We conclude that an antifungal drug directed against Fba1p would have to be potent to be effective.
引用
收藏
页码:1371 / 1377
页数:7
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