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Selective membrane toxicity of the polyene antibiotics: studies on lecithin membrane models (liposomes)
Abstract:
In the absence of sterol, amphotericin B at 5 x 10(-6) M caused maximum marker release from the saturated dipalmitoyl lecithin liposomes, minimum release from the unsaturated dioleoyl lecithin liposomes, and an in-between response from egg lecithin liposomes. Nystatin at 2.5 to 4.0 x 10(-5) M induced appreciable marker release from all three types of sterol-free liposomes. The amphotericin B- and nystatin-induced permeability changes in dipalmitoyl lecithin liposomes were drastically suppressed by the incorporation of cholesterol or stigmasterol (with identical Delta5 sterol nuclei), but were unaffected by the incorporation of ergosterol or 5,7-cholestadien-3beta-ol (with identical Delta5,7 sterol nuclei). The nystatin sensitivity of dioleoyl lecithin liposomes remained low after the incorporation of cholesterol or stigmasterol, but was greatly enhanced by the incorporation of ergosterol or 5,7-cholestadien-3beta-ol. Digitonin, a compound known to interact specifically with membrane sterol, induced marker release from liposomes in proportion to the amount of either cholesterol or ergosterol incorporated; epicholesterol did not sensitize to digitonin. These results lead to the following conclusions: (i) polyene-induced permeability alteration in model membrane systems is effected by the composition of membrane phospholipid fatty acyl chains; (ii) the distribution of double bonds in the sterol nucleus is related to the selective toxicity of the polyenes toward natural sterol-containing membranes; and (iii) polyenes differ in membrane selectivity.
Insights
Polyene antibiotics like amphotericin B and nystatin alter liposome permeability, with effects depending on phospholipid and sterol composition. Sterol structure, particularly double bond placement, dictates selective toxicity of these antifungal agents.
Area of Science:
- Biochemistry
- Membrane Biophysics
- Pharmacology
Background:
- Polyene antifungals interact with sterols in cell membranes.
- Liposomes serve as model systems to study drug-membrane interactions.
- Understanding polyene selectivity is crucial for developing targeted therapies.
Purpose of the Study:
- To investigate the influence of phospholipid and sterol composition on polyene antibiotic-induced liposome permeability.
- To elucidate the structural basis for selective toxicity of polyenes.
Main Methods:
- Liposomes composed of dipalmitoyl lecithin, dioleoyl lecithin, or egg lecithin were prepared.
- Sterols (cholesterol, stigmasterol, ergosterol, 5,7-cholestadien-3beta-ol, epicholesterol) were incorporated into liposomes.
- Marker release assays were performed to measure liposome permeability changes induced by amphotericin B, nystatin, and digitonin.
Main Results:
- Amphotericin B and nystatin induced marker release from sterol-free liposomes, with varying efficacy based on phospholipid unsaturation.
- Cholesterol and stigmasterol suppressed polyene-induced permeability changes in saturated liposomes.
- Ergosterol and 5,7-cholestadien-3beta-ol enhanced nystatin sensitivity in unsaturated liposomes.
- Digitonin-induced release correlated with cholesterol and ergosterol content, but not epicholesterol.
Conclusions:
- Polyene-induced membrane permeability changes are influenced by phospholipid fatty acyl chain composition.
- Sterol nucleus double bond distribution is critical for selective polyene toxicity.
- Different polyene antibiotics exhibit distinct membrane selectivity profiles.