The common use of antibacterial antibiotics and several modern medical technologies giving rise to attenuation of human immunological system, have caused a substantial increase in frequency of disseminated mycoses. These infections are nowadays considered a serious clinical problem, due to the high mortality rate, limited number of effective antifungal drugs and high level of antifungal drug resistance [1]. Search for new antifungals, especially targeting novel molecular targets in fungal cells, is therefore an urgent need.
The fungal enzyme, glucosamine-6-phosphate (GlcN-6-P) synthase, catalysing a crucial reaction in the cell wall biosynthesis, is known as potential target for antifungal chemotherapy and  N³-(4-methoxyfumaroylo)-L-2,3-diaminopropanonic acid (FMDP) is an effective and selective inhibitor of this enzyme [2]. Unfortunately FMDP is a highly hydrophilic molecule and is poorly taken up by fungal cells.
In the present communication we present construction of highly effective antifungal agents by incorporation of FMDP into oligopeptide carriers composed of 5-10 proteinogenic amino acid residues. These oligopeptide carriers are amphipatic and contain basic amino acids (Lys and Arg) and amino acids with hydrophobic side chains. FMDP-oligopeptide conjugates exhibit strong antifungal in vitro activity, at least two orders of magnitude better than FMDP alone. Evidence confirming that the conjugates obtained effectively penetrate fungal cells, are splitted inside to generate the active inhibitor of GlcN-6-P synthase and finally their action causes destruction of fungal cells, are presented.

References:

[1] M. T. Baixench, N. Aoun, M. Desnos-Ollivier, D. Garcia-Hermoso, S. Bretagne, S. Ramires, C. Piketty, E. Dannaoui, J. Antimicrob. Chemother., 59, 1076 (2007)
[2] H. Chmara, R. Andruszkiewicz, E. Borowski, Biochem. Biophys. Res. Commun., 16, 865 (1984)

This work was supported by the UMO-2012/05/B/ST5/00291 grant from the National Science Centre

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1. Synthesis and biological activity of N³-(4-metoxyfumaroyl)-L-2,3-diamiopropanoic acids (FMDP)  glycolamides and lactamides
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