Polyene antibiotics membrane interaction

AndreollTE. On the anatomy of amphotericin B-cholesterol pores in lipid bilayer membranes. Kidney Int 1973 4 337-45. DeKruijiff B, Demel RA. Polyene antibiotic-sterol interactions in membranes of Acholeplesma laidlawii cellsand lecithin liposomes. III. Molecular structure of the polyene antibiotic-cholesterol complexes. Biochem Biophys Acta 1974 339 57-70. HoIzRW.Theeffectsofthe polyene antibiotics nystatin and amphotericin Bon thin lipid membranes. Ann N Y Acad Sell 974 235 469-79. 

Amphotericin B, is a polyene antibiotic, used in the therapy of systemic fungal infections. Its mode of action exploits differences in membrane composition between the pathogen and the human host. Ergosterol, the predominant sterol of fungi, plants, and some protozoan parasites, interacts with Amphotericin B, resulting in an increased ion permeability of the membrane. Humans contain cholesterol, which has a low affinity for amphotericin B. 

The mixing of nematogenic compounds with chiral solutes has been shown to lead to cholesteric phases without any chemical interactions.147 Milhaud and Michels describe the interactions of multilamellar vesicles formed from dilauryl-phosphotidylcholine (DLPC) with chiral polyene antibiotics amphotericin B (amB) and nystatin (Ny).148 Even at low concentrations of antibiotic (molar ratio of DLPC to antibiotic >130) twisted ribbons are seen to form just as the CD signals start to strengthen. The results support the concept that chiral solutes can induce chiral order in these lyotropic liquid crystalline systems and are consistent with the observations for thermotropic liquid crystal systems. Clearly the lipid membrane can be chirally influenced by the addition of appropriate solutes. 

Bolard J, Seigneuret M, Boudet G. Interaction between phospholipid bilayer membranes and the polyene antibiotic amphotericin B lipid state and cholesterol content dependence. Biochim Biophys Acta 1980 599 280. 

Andreoli, T. E., Monahan, M. (1968). The interaction of polyene antibiotics with thin lipid membranes, J. Gen. Physiol, 52 300. 

Filipin (315) is a polyene antibiotic that is capable of interaction with sterols in liposomes and biological membranes, leading to alteration of... 

In contrast to lipid bilayer membranes, it has been found [4] that the permeability coefficient of the human red-cell membrane to water did not change when the free cholesterol content in the membrane was varied from 0.84 to 1.87 mg/ml cells. Furthermore, the permeability of the human red-cell membrane to sulfate and some nonelectrolytes remained constant when membrane cholesterol was partially removed (for review, see [6]). These results, however, should not be taken as evidence that water transport in human red cells is independent of membrane cholesterol, since this degree of variation may be insufficient to produce alteration. In fact, extensive depletion of membrane cholesterol induces a marked increase in nonelectrolyte permeability. The effect of membrane cholesterol on the transport of water is also found in other membrane systems. For example, the polyene antibiotic. Amphotericin B, which interacts specifically with sterol-containing membranes, increases the permeability of the mucosal but not the serosal membrane of toad bladder to water and other solutes [32]. It is possible that membrane cholesterol only effects the movements through the lipid bilayer pathway. This may explain the findings that the permeabiUty coefficient of the human red cell membrane to water... 

These polyenes injure fungi by binding to the ergosterol and sitosterol of the plasma membranes (Hamilton-Miller, 1973). Mycoplasma laidlawii was unaffected by filipin when grown in the absence of the sterol, but lysed when grown in its presence (Weber and Kinsky, 1965). When polyene antibiotics were injected under mixed lipids, present as a monolayer in a surface-trough, it was found that the polyene interpenetrated the film and increased its area. Reorientation of the sterol component, caused by interaction with the polyene, seemed to make the film leaky (Demel, Van Deenen and Kinsky, 1965). Mitochondrial and nuclear membranes are not affected by the polyenes, nor is the cell wall (Kinsky, 1962). 

Sterols are not the only conceivable membrane constituent which have been reported to antagonise polyenes or inhibit polyene binding. Similar effects have also been reported for oleic acid, linoleic acid, vitamin A, and lecithins [162, 165-169]. Such compounds may compete with sterol in the cell membrane for available polyene molecules or more likely bind to the cell surface, and there they either interact with the polyene antibiotic or mask sterol molecules in the membrane, thereby reducing the number of binding sites. It has been shown that... 

The nature of the interaction between polyene antibiotics and membrane sterols has also been investigated using UV, fluorescence and circular dichroism spectral studies [155,159,187,188]. The rate and degree of filipin III binding to cholesterol-containing liposomes depended upon the absolute sterol concentration and the mole percent in the bilayer. Binding constants for filipin III and liposomes were also estimated. 

The antimicrobial action of polyenes depends upon hydrophobic interaction between the antibiotic and membrane-located sterols. The use of polyene antibiotics in topical and especially systemic antifungal therapy depends upon the greater binding affinity between the polyene and fungal ergosterol than that between the antibiotic and mammalian cholesterol. Filipin and amphotericin illustrate two extremes of polyene action. 

The principle of the fungistatic activity of both the saponins and the polyene antibiotics is an interaction with fungal membrane sterols, and probably with proteins and phospholipids [1,6]. Organisms which have no sterols In their membranes are not sensitive to saponins or polyene antibiotics [6,7]. Electron micrographs of the membranes of erythrocytes [2,6] or yeasts [8,9,10] treated with saponin or polyene antibiotics show convincingly the destruction of the membrane, but the sterol-saponin or sterol-polyene complex has not yet been isolated and determined. 

Nystatin (Fig. 2.18), a macrocydic polyene antibiotic, is an example of a drug with an extended system of double bonds. The double bonds interact with membrane lipids. 

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