Antifungal conjugates incorporating N5-acetyl-N5-hydroxy-L-ornithine as a molecular carrier.

A simplified, artificial siderophore, N5-acetyl-N5-hydroxy-L-ornithine (AHO), can be used as a molecular carrier for the construction of the Trojan Horse-type conjugates exhibiting antifungal activity. Rationally designed AHO-incorporating conjugates with 4-cyano-tryptophan were effectively transported and accumulated in human pathogenic yeasts, especially Candida albicans and Candida glabrata (Nakaseomyces glabratus), known to express the Sit1/Arn1 hydroxamate siderophore uptake system. The AHO-containing conjugates with cispentacin (CP) demonstrated antifungal in vitro activity, particularly against C. albicans and C. glabrata. The antifungal effect of AHO: TML: CP congeners, containing esterase-cleavable trimethyl lock (TML) linker, was substantially higher than that of their AHO: CP counterparts. The latter conjugates were poorly cleaved in the cell-free extract of C. albicans cells. The lowest MIC90 values, namely 16–32 µg mL− 1, were found for TML-containing CP conjugates in iron-deprived growth media, i.e. under conditions stimulating expression of the inducible systems of iron acquisition.