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.
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.
Rodaki
Alexandra
A
Aberdeen Fungal Group, School of Medical Sciences, Institute of Medical Sciences, University of Aberdeen, Aberdeen AB25 2ZD, United Kingdom.
Young
Tim
T
Brown
Alistair J P
AJ
D000818:Animals; D000935:Antifungal Agents / Q000627:therapeutic use*; D001483:Base Sequence; D002176:Candida albicans / Q000201:enzymology* / Q000235:genetics / Q000254:growth & development*; D002177:Candidiasis / Q000188:drug therapy*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D005634:Fructose-Bisphosphate Aldolase / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D008715:Methionine / Q000494:pharmacology; D051379:Mice; D008826:Microbial Sensitivity Tests; D008969:Molecular Sequence Data
D000935:Antifungal Agents; D008715:Methionine; D005634:Fructose-Bisphosphate Aldolase