Effects of Archaeal Tetraether Lipids on Membrane Partitioning of the Antifungal Drug Nystatin

Abstract

Nystatin is a polyene antibiotic that is frequently used in the treatment of cutaneous, vaginal, and oral fungal infections. It interacts with ergosterol in the fungal cell plasma membrane, causing membrane disruption and leakage, and leading to cell death. Liposomal nystatin has good antifungal activity but with significantly less systemic toxicity compared to free nystatin. In this study, we attempt to use archaeal tetraether lipids to increase the stability and drug loading of liposomal nystatin. Using a fluorometric method, we have determined the partition coefficient of nystatin into liposomes composed of cholesterol and POPC (80 mol%) in the absence and presence of archaeal tetraether lipids. We found that nystatin partition into liposomes increases significantly (by a factor of ∼4-10) with the addition of 0.5 mol% archaeal tetraether lipids PLFE to replace 0.5 mol% cholesterol. PLFE is the polar lipid fraction E isolated from the thermoacidophilic archaeon Sulfolobus acidocaldarius. This dramatic change in nystatin partitioning engendered by PLFE was surprising and may result from the presence of interfacial regions between diester and tetraether lipid domains. This result plus our previous findings in PLFE-enhanced membrane stability suggest that tetraether lipids can be a useful additional component in liposomal nystatin formulations.