1887

Abstract

-(4-Methoxyfumaroyl)--2,3-diaminopropanoic acid (FMDP), a specific and potent inactivator of glucosamine-6-phosphate (GlcN-6-P) synthase from , exhibits relatively poor anticandidal activity, with an MIC value amounting to 50 μg ml (200 μM). Uptake of FMDP into cells follows saturation kinetics and is sensitive to the action of metabolic inhibitors, thus indicating the active transport mechanism. However, the acetoxymethyl ester of FMDP penetrates the fungal cell membrane by free diffusion and is rapidly hydrolysed by cytoplasmic enzymes to release the free FMDP. This mechanism gives rise to continuous accumulation of the enzyme inhibitor and results in higher antifungal activity of the FMDP ester (MIC=31 μg ml, 10 μM). These results show that the ‘pro-drug’ approach can be successfully applied for the enhancement of antifungal activity of glutamine analogues that inhibit GlcN-6-P synthase.

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2001-07-01
2020-01-27
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