Interaction of Amphotericin B with Cholesterol in Monolayers, Aqueous Solutions, and Phospholipid Bilayers

Abstract

The interaction of amphotericin B (AmB) with cholesterol was investigated in monolayers, aqueous solutions, and phospholipid vesicles. When AmB was mixed with cholesterol, it formed a stable monolayer, implying complex formation in which the stoichiometry was primarily 1:1 AmB:cholesterol. However, the interaction of AmB with cholesterol in aqueous solutions and lipid vesicles was more complex. In aqueous solutions, cholesterol at low concentrations increased the aggregation of AmB. But higher concentrations of cholesterol caused dissociation of the aggregates of AmB due to the formation of AmB-cholesterol complexes. In lipid vesicles, the effect of cholesterol was different from that in aqueous solutions. Both in aqueous solutions and lipid vesicles, the overall dissociation of AmB molecules occurred on interaction with cholesterol. In addition, the interaction of lipid membranes with AmB-cholesterol complexes was investigated by differential scanning calorimetry. The incorporation of AmB into lipid bilayers led to broadening of the lipid transition and a slight decrease in the transition enthalpy, showing that one lipid molecule per AmB molecule was immobilized. However, the number of immobilized lipid molecule per AmB molecule increased in the coexistence of cholesterol, due to the complex formation between AmB and cholesterol.

Amphotericin B−Dipalmitoyl Phosphatidyl Glycerol Interactions Responsible for the Reduced Toxicity of Liposomal Formulations: A Monolayer Study

“…Therefore, when amphotericin B is administered in the form of fungizone (free AmB), both ergosterol and phospholipid molecules compete with each other to form complexes with AmB. Since the AmB affinity for ergosterol is higher − than that for the phospholipid, , channelsformation is induced in the fungi membrane which eventually leads to the cells' death (Figure A). In the case of mammalian cellular membrane (containing cholesterol instead of ergosterol), the interactions between cholesterol and the phospholipid are very strong , and the equilibrium is shifted to the left-hand side.…”

Ion Channel Behavior of Amphotericin B in Sterol-Free and Cholesterol- or Ergosterol-Containing Supported Phosphatidylcholine Bilayer Model Membranes Investigated by Electrochemistry and Spectroscopy

“…When the AmB concentration was increased, all the peaks enhanced their intensity and the 340-nm peak increased in a drastic way without a shift in their position. The 340-nm peak is regarded as characteristic of aggregates in which the polyene chromophores are stacked so as to interact electronically (Bolard, 1991;Fujii et al, 1997;Saka and Mita, 1998;Tancre `de et al, 1990) On the other hand, a 408-nm peak is regarded as characteristic of monomers (Barwicz et al, 1998;Bolard, 1986;Chapados et al, 1994;Madden et al, 1990). The absorption spectra change with AmB concentration is due to a displacement of the equilibrium between monomer and aggregate.…”

Micelle-like Nanoassemblies of Short Peptides Create Antimicrobial Selectivity in a Conventional Antifungal Drug

“…A dispersant such as deoxycholic acid or liposomes is currently required to formulate AmB. Second, AmB has nonspecific toxicity toward fungi and normal tissues. , AmB binds preferably to ergosterol, which exists only in cell membranes of fungi, and forms a channel in the cell membrane to disrupt the ion balance of fungus cells. , AmB exhibits a weak affinity to cholesterol in mammalian cell membranes, which results in side effects in the tissues of treated patients. Additionally, treatment with AmB poses a potential health risk because this drug may completely eradicate indigenous fungi in patients because of a lack of specificity toward fungal species.…”