Solid-phase synthesis and antimicrobial activities of lipid-neomycin conjugates

Lipid linked aminosugars have been shown to have significant antimicrobial properties. We report here a solid phase strategy for the rapid synthesis of lipid-aminoglycoside compounds, linked with amino acids. Subsequent screening of the compounds against pathogens known to cause clinical fungal infections is also reported herein. We have screened the library for antifungal activity in eight species of Candida. The lipid-neomycin conjugates show antifungal minimal inhibitory concentrations in the 1.56-3.13 μM range across a broad spectrum of Candida. Generally, conjugates with long chain lipids were much more effective antifungals than those with short chain lipids or lipids with multiple double bonds, and this work therefore targets the synthesis and screening of such long chain saturated compounds. The methods presented here are equally suitable for synthesis of any lipid aminoglycoside combination, efficiently combining lipids and carbohydrates via peptides using solid phase synthesis. The strategy also allows easy manipulation of the linker lengths and hydrophobicities for linkers that combine the lipid to the sugar.