amphotericin-b and 1-2-oleoylphosphatidylcholine

Amphotericin B, an acquainted antifungal drug, has reattracted the attention of most scholars due to its one important advantage of making the fungus less resistant. Amphotericin B's antifungal properties are derived from its ability to interact with ergosterols on the fungal cells' membrane to form pores. However, the cholesterol in the human cell membranes is similar in structure to ergosterol, which cause the drug to produce certain toxicity and make the clinical use of amphotericin B limited. The study of the interaction between amphotericin B and lipid monolayer in the presence of cholesterol or ergosterol is crucial to understanding the mechanism of effect of the drug on cell membranes. Langmuir monolayer as a model for half of cell membranes can precisely control the proportion of components and the solution environment, which has been used to do a lot of research about the interaction of amphotericin B with lipids. It is noteworthy that some ions associated with life activities play an important role in it, such as calcium ions. In this work, the surface pressure-mean molecular area isotherms, elastic modulus and the surface pressure-time curves of DPPC/DOPC/sterol mixed monolayer with or without amphotericin B were studied in the different concentration of calcium ions. The morphology of the Langmuir-Blodgett films transferred on the mica were observed by atomic force microscopy. The results shown that AmB changed the elastic modulus and surface morphology of DPPC/DOPC/sterol mxied monolayer, which was significantly different with different types of sterols. Calcium ions can regulate the effect of this drug, which was clearly different due to different types of sterols. This work provides useful information to further understand the influence mechanism of calcium ions on the interaction between AmB and phospholipid/sterol monolayer, which is helpful to find out the effect mechanism of calcium ion on the interaction between AmB and phospholipid monolayer containing ergosterol or cholesterol and to understand the mechanism of AmB influencing on the membrane of fungal or human cells.

Topics: Amphotericin B; Calcium; Humans; Ions; Phosphatidylcholines; Sterols

A model lipid membrane consisting of a monolayer of dioleoyl phosphatidylcholine (DOPC) adsorbed onto a Hg electrode has been used to study the interaction between the lipid and different formulations of Amphotericin B (AmB) [Fungizone (FZ), Heated Fungizone (HFZ), and Abelcet]. The lipid organizational order was measured by electrochemical methods [capacitance and metal ion (Tl(+)) reduction], characterizing the change in lipid order due to interaction with the drug. The mean size and number density of pores formed in the monolayer were estimated by fitting the reduction current transients to a random array of microelectrode model. This method was shown sensitive for investigation of the interaction of drugs with the DOPC monolayer. Abelcet was found to have a smaller disruptive effect on lipid order than FZ and HFZ. The formulations used to solubilize the AmB were also studied. Sodium deoxycholate used as a solubilizer in FZ displayed significant influence on lipid order similar to that observed for Abelcet. The lipid complex, used in Abelcet, did not significantly perturb the DOPC monolayer order. The lipid complex used in Abelcet may have an annealing or healing effect that buffers the disruption possible due to AmB.

Topics: Amphotericin B; Antifungal Agents; Chemistry, Pharmaceutical; Drug Combinations; Electrochemistry; In Vitro Techniques; Membrane Lipids; Phosphatidylcholines; Phosphatidylglycerols

Amphotericin B (AmB) is the most effective antibiotic used in the treatment of systemic fungal infections. It is generally thought that the activity of this drug results from its interaction with ergosterol, the main sterol of fungi membranes. However, AmB also interacts with cholesterol, the major sterol of mammal membranes, thus limiting the usefulness of this drug due to its relatively high toxicity. The aim of the present work is to study the molecular basis of the interactions of AmB with these sterols contained in a DOPC film by using the monolayer technique. Two different concentrations of the sterols in the film (13 and 30%) at an initial surface pressure of 30 mN/m were studied, which correspond to conditions found in various biological membranes. Four concentrations of AmB in the subphase, ranging from a molecularly dispersed to a highly aggregated state of the drug were studied. Our results show that the monomeric form of AmB interacts with the ergosterol containing film solely. On the other hand, when AmB is dispersed as a pre-micellar or as a highly aggregated state in the subphase, a very significant selectivity of its interactions between the two sterols is observed which is shown in our experimental results by a difference of 8 mN/m in the surface pressure when AmB interacts with ergosterol as compared to cholesterol. We show that the activity of AmB is most likely related to the micellar form of the antibiotic. In addition, we observe that upon increasing the amount of ergosterol in the film, the insertion of AmB is largely promoted, results that are discussed in terms of the molecular organization of the sterols within the monolayer film. We show that these results provide a better understanding of the action of AmB (activity/toxicity) at the membrane level.

Topics: Adsorption; Amphotericin B; Cholesterol; Ergosterol; Membranes, Artificial; Micelles; Phosphatidylcholines; Surface Properties

Topics: Amphotericin B; Computer Simulation; Models, Molecular; Molecular Structure; Phosphatidylcholines; Software

It has generally been assumed that the polyene antibiotics Nystatin and Amphotericin B cause membrane damage by the same mechanism. However, using kinetic fluorescence methods we have found that AmB and Nystatin have very different activities on sterol-free dioleoyl phosphatidylcholine and egg phosphatidylcholine small unilamellar vesicles. At very low AmB concentrations (less than 1/1000 lipids in egg phosphatidylcholine) significant K+ permeability enhancement is observed. However, even at very high Nystatin to lipid ratios (1/100) very little K+ current is induced, particularly in dioleoyl phosphatidylcholine vesicles. The novel technique described here uses a K+/H+ exchange mechanism to detect minute transmembrane K+ currents by monitoring internal membrane vesicle pH changes with pyranine.

Topics: Amphotericin B; Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone; Hydrogen-Ion Concentration; Kinetics; Liposomes; Models, Biological; Nystatin; Permeability; Phosphatidylcholines; Potassium