Recent progress in the study of the interactions of amphotericin B with cholesterol and ergosterol in lipid environments

European Biophysics Journal, Sep 2014

In the past decade substantial progress has been made in understanding the organization and biological activity of amphotericin B (AmB) in the presence of sterols in lipid environments. This review concentrates mainly on interactions of AmB with lipids and sterols, AmB channel formation in membranes, AmB aggregation, AmB modifications important for understanding its biological activity, and AmB models explaining its mechanism of action. Most of the reviewed studies concern monolayers at the water–gas interface, monolayers deposited on a solid substrate by use of the Langmuir–Blodgett technique, micelles, vesicles, and multi-bilayers. Liposomal AmB formulations and drug delivery are intentionally omitted, because several reviews dedicated to this subject are already available.

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Recent progress in the study of the interactions of amphotericin B with cholesterol and ergosterol in lipid environments

Daniel Micha Kaminski 0 ) Department of Chemistry, University of Life Sciences in Lublin , Akademicka 15, 20-950 Lublin, Poland In the past decade substantial progress has been made in understanding the organization and biological activity of amphotericin B (AmB) in the presence of sterols in lipid environments. This review concentrates mainly on interactions of AmB with lipids and sterols, AmB channel formation in membranes, AmB aggregation, AmB modifications important for understanding its biological activity, and AmB models explaining its mechanism of action. Most of the reviewed studies concern monolayers at the watergas interface, monolayers deposited on a solid substrate by use of the Langmuir-Blodgett technique, micelles, vesicles, and multi-bilayers. Liposomal AmB formulations and drug delivery are intentionally omitted, because several reviews dedicated to this subject are already available. - Amphotericin B (AmB) is a macrolide polyene antifungal antibiotic (Gallis et al. 1990; AbuSalah 1996; Hartsel and Bolard 1996; Carrillo-Munoz et al. 2006; Cereghetti and Carreira 2006). The number of research papers published in recent years on its pharmacological properties, clinical therapeutic effects, and toxicity is evidence of the importance of AmB in contemporary medicine (Brajtburg et al. 1990; Tiphine et al. 1999; Fanos and Cataldi 2000; Lemke et al. 2005; Fanos et al. 2007; Moen et al. 2009; Hamill 2013). AmB, a metabolite of Streptomyces nodosus, causes disintegration of the fungal lipid membranes. These membranes contain ergosterol, which, similar to cholesterol, changes dynamic properties and stabilizes lipid bilayer structure. AmB has better selectivity for membranes containing ergosterol than for those containing cholesterol. This property enables use of the drug to treat deep fungal infections that occur in the aftermath of AIDS or transplantation. Despite its antifungal activity, AmB has many sides effects which are most probably related to AmBcholesterol interactions (Wilcock et al. 2013). In addition, AmB has several side effects because of formation of aqueous pores (Cohen 1998); among these, nephrotoxicity (Fanos and Cataldi 2001) and hematotoxicity (Wong-Beringer et al. 1998) are the most serious. The AmB molecule comprises a macrolactone ring, which is -glycosylated at position C19 with a mycosamine group (Ganis et al. 1971; Jarzembska et al. 2012). The ring is an almost flat chromophore with seven conjugated double bonds in the trans conformation. The ring also contains a more flexible polyol subunit (Fig. 1). At positions C13 and C17, the macrolactone ring contains a hemiketal ring. The presence of a carboxyl group at C16 and an amino group in the mycosamine head group determines the amphoteric character of this molecule. In addition, the specific AmB three-dimensional structure which has well defined hydrophobic and hydrophilic regions is responsible for its amphipathic properties. Consequently, AmB is poorly soluble in highly polar and apolar solvents. For this reason, AmB tends to aggregate (Shervani et al. 1996) in highly polar solvents, for example water, which gives rise to a variety of models explaining its antifungal activity. Several possible mechanisms of action of AmB can be found in the literature. The first, oldest, and most studied is the ion-channel model proposed by Finkelstein and Holz Fig. 1 Schematic representation of sterols and amphotericin B Fig. 2 Models of amphotericin B function in phospholipid bilayers. a Classical-ion channel model in which AmB molecules aggregate in such a way that they form a barrel with their polyhydroxy chain groups pointing inward and their heptaene parts pointing outward. b Surface adsorption model in which AmB extracts ergosterol from the bilayer to the surface. c Sponge model in which large AmB aggregates extract ergosterol from the phospholipid membrane (1973) (Fig. 2a). According to this model, AmB molecules aggregate in such a way that they form a barrel through a bilayer with their polyhydroxy chain groups pointing inward and the heptaene parts pointing outward. Pores can be created in both leaflets of the bilayer, or half-pores can be formed which bond two sides of the bilayer (Fig. 2a). The pore can be formed from different numbers of monomers, ranging from 4 to 12 (Cass et al. 1970; Gruszecki et al. 2003), and this has been confirmed by channel-conductivity experiments (Brutyan and McPhie 1996; Cotero et al. 1998). These pores are responsible for leaking of K+ ions and small organic particles vital for cell function. The second concept is based on the oxidative cell damage caused by amphotericin B (Brajtburg et al. 1985; SokolAnderson et al. 1988), which affects fungi and causes lysis of red cells. This effect induces formation of reactive oxygen species, for example superoxide, hydrogen peroxide, and hydroxyl radicals, which oxidize the lipid membrane (Lamy-Freund et al. 1985). AmB can bond to low-density lipoprotein re (...truncated)


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Daniel Michał Kamiński. Recent progress in the study of the interactions of amphotericin B with cholesterol and ergosterol in lipid environments, European Biophysics Journal, 2014, pp. 453-467, Volume 43, Issue 10-11, DOI: 10.1007/s00249-014-0983-8