A diffusible analogue of N-3-(4-methoxyfumaroyl)-L-2,3-diaminopropanoic acid with antifungal activity

N-3-(4-Methoxyfumaroyl)-L-2,3-diaminopropanoic acid (FMDP), a specific and potent inactivator of glucosamine-6-phosphate (GlcN-6-P) synthase from Cand ida albicans, exhibits relatively poor anticandidal activity, with an MIC v alue amounting to 50 mug ml(-1) (200 muM). Uptake of FMDP into C. albicans cells follows saturation kinetics and is sensitive to the action of metabol ic inhibitors, thus indicating the active transport mechanism. However, the acetoxymethyl ester of FMDP penetrates the fungal cell membrane by free di ffusion and is rapidly hydrolysed by C. albicans cytoplasmic enzymes to rel ease 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 = 3.1 mug ml(-1), 10 muM). These results show that the 'pro-dru g' approach can be successfully applied for the enhancement of antifungal a ctivity of glutamine analogues that inhibit GlcN-6-P synthase.