Amphotericin B: Mechanism of Action

Amphotericin B is a polyene antifungal agent with a broad range of activity against yeasts and molds, as well as the protozoan parasite Leishmania spp. Liposomal amphotericin B (LAmB) binds to ergosterol in the fungal cell membrane leading to ion leakage and cell death. The initial formulation was amphotericin B deoxycholate (DAmB), which was developed in the 1950s. For many decades DAmB was the only antifungal agent available for the treatment of invasive fungal diseases. However, the significant dose-limiting toxicity of DAmB (most notably nephrotoxicity and infusion-related reactions) provided the impetus to develop new less toxic formulations. Liposomal amphotericin B (AmBisome®; LAmB) is a unique lipid formulation of amphotericin B that has been used for nearly 20 years to treat a broad range of fungal infections. While the antifungal activity of amphotericin B is retained following its incorporation into a liposome bilayer, its toxicity is significantly reduced.

Mechanism of Action

Amphotericin B binds to ergosterol in the fungal cell membrane, which leads to the formation of pores, ion leakage and ultimately fungal cell death. The binding of the liposome (both 'loaded' with amphotericin B and empty liposomes) to the cell wall of pathogenic yeasts and moulds has been demonstrated in vitro and in vivo using fluorescently labeled liposomes and gold-labeled liposomes. Liposomes without AmB bind to the fungal cell wall, but both the 'empty' liposomes and the fungal cell remain intact. In contrast binding of amphotericin B containing liposomes results in fungal cell death suggesting that binding results in liposomal disruption and release of amphotericin B, which is then free to exert its fungicidal activity by binding to ergosterol in the fungal cell membrane.

The precise mechanism by which amphotericin B is transferred from the liposome through the fungal cell wall to the fungal membrane is not known. It is likely that the process is facilitated by the higher binding affinity of amphotericin B for ergosterol (the sterol present in fungal cell membranes) compared with cholesterol, which is the principal lipid component of the liposome. Temperature also appears to be important in the transfer of amphotericin B between the liposome and the fungus and occurs most efficiently at body temperature.

Reference

[1] Stone NR, Bicanic T, Salim R, Hope W. Liposomal Amphotericin B (AmBisome(®)): A Review of the Pharmacokinetics, Pharmacodynamics, Clinical Experience and Future Directions. Drugs. 2016 Mar;76(4):485-500. doi: 10.1007/s40265-016-0538-7.

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