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.
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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)