Agenti antifungini

Amphotericin B is an amphipathic molecule with hydrophobic and hydrophilic regions that selectively bind to ergosterol, a sterol predominant in fungal plasma membranes. This binding exploits structural differences between fungal and mammalian cell membranes, enabling the drug to disrupt fungal cells while minimizing damage to human cells. The selective interaction with ergosterol underlies amphotericin B's antifungal activity.

In the pore-formation model, amphotericin B molecules insert into the lipid bilayer and assemble into pore-like channels. Multiple amphotericin molecules align with surrounding lipid chains to form these oligomeric transmembrane channels. The pores allow uncontrolled leakage of intracellular ions, particularly potassium, disrupting ionic gradients and causing fungal cell death.

In the surface-aligned model, amphotericin B binds ergosterol while remaining parallel to the membrane rather than inserting through it. This alignment causes ergosterol clustering at the membrane surface, disrupting lipid organization and compromising membrane integrity without forming pores. This mechanism operates independently of transmembrane channel formation.

Amphotericin B triggers production of reactive oxygen species (ROS), including superoxide anions, hydrogen peroxide, and hydroxyl radicals. These ROS cause oxidative damage to cellular components such as lipids, proteins, and nucleic acids. This oxidative stress mechanism operates independently of ergosterol binding, providing an additional fungicidal effect beyond membrane disruption.

In the sponge model, amphotericin B aggregates sequester ergosterol into extracellular complexes rather than embedding in the membrane. These aggregates extract ergosterol from the bilayer, depleting it and impairing essential membrane functions. This mechanism represents an alternative pathway to fungal cell death distinct from pore formation or surface alignment.

Although amphotericin B selectively binds ergosterol in fungal membranes, weak binding to cholesterol, the sterol predominant in mammalian cell membranes, contributes to toxicity in human cells. This off-target interaction with cholesterol can disrupt human cell membranes, limiting the drug's therapeutic window. The structural similarity between ergosterol and cholesterol accounts for this undesired cross-reactivity.

Amphotericin B's amphipathic structure features a hydrophobic polyene-lactone ring and a hydrophilic region containing mycosamine and carboxylic acid groups. The mycosamine and carboxylic acid groups bind to ergosterol, stabilizing the molecule's insertion into the fungal lipid bilayer. This dual-region architecture allows selective recognition and targeting of fungal-specific membrane components.