Role of the Sterol Superlattice in the Partitioning of the Antifungal Drug Nystatin into Lipid Membranes^,

Abstract

Nystatin isolated from Streptomyces is a polyene antibiotic that is frequently used in the treatment and prophylaxis of fungal infections. Here, the fractional sterol concentration dependencies of the partition coefficient for partitioning of nystatin into ergosterol/dimyristoyl-L-alpha-phosphatidylcholine (DMPC), cholesterol/DMPC, ergosterol/1-palmitoyl-2-oleoyl-L-alpha-phosphatidylcholine (POPC), and ergosterol/POPC/1-palmitoyl-2-oleoyl-L-alpha-phosphatidylethano lam ine (POPE) multilamellar vesicles have been determined fluorometrically at 37 degrees C using approximately 0.3-1.0 mol % sterol concentration increments over a wide concentration range (e.g., 18-54 mol % sterol). This unconventional approach of varying membrane sterol content, in contrast to previous studies using large sterol concentration increments (e.g., 10 mol %), leads to a striking observation. The partition coefficient of nystatin changes dramatically with membrane sterol content in a well-defined alternating manner, displaying a local minimum at or very close to the critical sterol mole fractions (e.g., 20.0, 22.2, 25.0, 33.3, 40.0, and 50.0 mol % sterol) predicted for sterols regularly distributed in either hexagonal or centered rectangular superlattices. In ergosterol/DMPC bilayers, for example, there is a >3-fold increase in nystatin partitioning with a minute change (approximately 1 mol %) in sterol content on either side of the critical sterol mole fraction, 25.0 mol %. These results provide semifunctional evidence supporting the sterol regular distribution model [Chong, P. L.-G. (1994) Proc. Natl. Acad. Sci. U.S.A. 91, 10069-10073]. More importantly, these results reveal a new membrane phenomenon, that is, that nystatin partitioning is affected by the extent of sterol regular distribution in the plane of the membrane. This phenomenon occurs not only in saturated (e.g., DMPC) but also in unsaturated (e.g., POPC) lipid membranes, and persists in the presence of polar headgroup heterogeneity (e.g., POPC/POPE). This membrane property points to a new method for studying the interactions of polyene antibiotics with sterol-containing membranes, and the need to consider the membrane sterol content of the target cells when administering nystatin or other polyene antibiotics.

Electric field effect on cholesterol–phospholipid complexes

“…As noted earlier, there is a long history of proposals for ''complex'' formation as well as for lattice-like structures in monolayers and bilayers (1,(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31). We make no distinction between a complex and a molecular lattice with short-range order.…”

A Statistical Mechanical Model of Cholesterol/Phospholipid Mixtures: Linking Condensed Complexes, Superlattices, and the Phase Diagram

“…The proportion of the densely packed area has been measured at different cholesterol mole fractions in cholesterol/DMPC and cholesterol/1-palmitoyl-2-oleoyl- sn -3-phosphocholine (POPC) mixtures 13-14 . Figure 3 shows the measured A reg values at six critical mole fractions ( x ) and calculated A reg vs. X c curves at several critical mole fractions (green lines).…”

“…x: measured local maxima of the regular area fraction 13 ; green lines: the curve of regular area fractions calculated by Eq.18. Dashed line: cholesterol precipitates from the bilayer above this mole fraction (as noted in the text, this actual limit is characteristic for cholesterol/PC bilayers).…”

Mutations in Yeast ARV1 Alter Intracellular Sterol Distribution and Are Complemented by Human ARV1

“…Interestingly, arv1⌬ cells are sensitive to nystatin (Fig. 1A), a polyene antibiotic that disrupts membranes in part by interaction with sterols (34). Because nystatin partitioning into membranes is sensitive to both sterol organization and levels (34) we analyzed sterol levels in these cells as reflected by incorporation of [ 3 H]acetate during exponential growth.…”