Increased Degree of Unsaturation in the Lipid of Antifungal Cationic Amphiphiles Facilitates Selective Fungal Cell Disruption

Fungal infections are an increasing problem in developed countries and in regions with limited healthcare availability. Mortality due to invasive fungal diseases likely exceeds that of tuberculosis or malaria with Candida and Cryptococci species the most frequently treated opportunistic fungal pathogens. Inspired by antimicrobial cationic peptides, we have developed several families of synthetic aminoglycoside-derived cationic amphiphiles. We demonstrated that by manipulating structural motifs it is possible to enhance the selectivity of these agents for microbial relative to mammalian red blood cell membranes.

Here we report that incorporation of double bonds, in particular cis-double bonds, into the lipids of cationic amphiphiles derived from the aminoglycoside antibiotic tobramycin significantly decreased hemolysis and toxicity toward mammalian cells and did not alter their antifungal activity against Candida and Cryptococcus neoformans relative to that of the parent amphiphile. One of the cationic amphiphiles with a linolenic acid lipid residue, containing three cis-double bonds, displayed no cytotoxicity against a panel of mammalian immortalized cell lines and primary cells. This compound also selectively eradicated C. albicans cells but did not affect the viability of human cells in co-culture experiments. Our findings offer a promising strategy for the development of non-toxic antifungal agents safe for systemic use.