Amphotericin B is an antifungal medication belonging to the polyene class, reserved for treating serious systemic fungal infections. The medication is administered intravenously to combat a wide range of fungal pathogens, including various species of Aspergillus, Candida, and the organism responsible for cryptococcal meningitis. Its discovery originated from a soil sample from the Orinoco River region in Venezuela, which contained the Streptomyces nodosus bacterium that produces it.
The Pore Formation Mechanism
The mechanism of amphotericin B begins at the fungal cell membrane, a lipid bilayer that gives the cell structure and regulates the passage of substances. Embedded within this lipid environment are various proteins and a type of sterol molecule called ergosterol. Ergosterol is a component of fungal cell membranes, where it modulates membrane fluidity and integrity, similar to how cholesterol functions in animal cells.
Amphotericin B is an amphipathic molecule, meaning it has both a water-loving (hydrophilic) and a water-fearing (hydrophobic) section. This dual nature allows it to insert itself into the lipid bilayer of the fungal membrane. The drug’s hydrophobic portion is drawn to and binds with high affinity to the ergosterol molecules within the membrane. This initial binding begins the process that leads to the fungal cell’s destruction.
Once a single amphotericin B molecule has anchored itself to an ergosterol molecule, it begins an aggregation process. Several more amphotericin B-ergosterol complexes are recruited to the site, arranging themselves into a circular, barrel-like structure that spans the entire width of the cell membrane. This structure forms a transmembrane channel or pore, punching a hole through the fungal cell’s protective barrier. This action can be visualized as poking numerous small holes in a water balloon, causing its contents to leak out uncontrollably.
The creation of these pores has significant consequences for the fungal cell. The channels disrupt the membrane’s ability to maintain a controlled internal environment. Monovalent ions, particularly potassium (K+), as well as sodium (Na+) and hydrogen (H+) ions, leak out of the cell through these newly formed passages. This efflux of ions leads to a depolarization of the membrane and ultimately causes the fungal cell to die. In addition to pore formation, some evidence suggests that amphotericin B can also induce oxidative damage, further contributing to cell death.
Selective Targeting of Fungal Cells
The effectiveness of amphotericin B lies in its ability to selectively target fungal pathogens over human cells. The basis for this targeting is the molecular difference between their membranes. Fungal cell membranes are rich in ergosterol, while human cell membranes use cholesterol. Amphotericin B has a much stronger binding affinity for ergosterol compared to cholesterol.
This preferential binding ensures that the pore formation process is concentrated on the invading fungal cells. As a result, the drug can disrupt and kill the fungal pathogens without causing widespread damage to the patient’s own cells. This selective action is what makes it a viable treatment for severe internal fungal infections.
Basis for Drug Toxicity
Despite its preference for fungal cells, amphotericin B is well-known for its significant side effects, which stem directly from its mechanism of action. The drug’s selective toxicity is not perfect, and its capacity to harm human cells is a primary limitation on its use. This toxicity stems from its ability to interact with cholesterol, the main sterol found in mammalian cell membranes.
While amphotericin B binds to ergosterol with high affinity, it can also bind to cholesterol, albeit with a lower affinity. When the concentration of the drug is high enough, this off-target binding becomes more frequent and can lead to the formation of pores in human cell membranes, mirroring the effect it has on fungi. This action disrupts the normal function of human cells by causing them to leak essential ions.
This off-target effect is particularly pronounced in tissues that have cholesterol-rich cell membranes, such as the kidneys. The formation of pores in the cells of the kidney tubules causes the drug’s most common and serious side effect: nephrotoxicity, or kidney damage. This can lead to imbalances in electrolytes, like the loss of potassium and magnesium, and can impair the kidney’s ability to filter waste from the blood. The infusion process itself can also trigger reactions like fever and chills as the drug interacts with host cells.
The likelihood of side effects requires careful patient monitoring, including regular checks of kidney function and electrolyte levels.
Clinical Use and Formulations
Amphotericin B is used for severe invasive fungal infections, such as systemic aspergillosis, cryptococcal meningitis, and disseminated candidiasis. For decades, the standard formulation was amphotericin B deoxycholate, a version known for its effectiveness but also for its significant risk of kidney damage.
To address the toxicity issues associated with the conventional formulation, lipid-based formulations of amphotericin B have been developed. These systems mitigate the drug’s harmful side effects while preserving its antifungal potency. The most common of these are liposomal amphotericin B (L-AMB) and amphotericin B lipid complex (ABLC).
These formulations work by encapsulating the amphotericin B molecule within a lipid sphere or ribbon. This packaging alters the drug’s distribution in the body, helping to shield cholesterol-rich human cells from direct exposure. The lipid carriers are thought to preferentially deliver the drug to sites of infection, where it acts on the fungal cells.
Clinical evidence has shown that these lipid formulations significantly reduce the incidence and severity of nephrotoxicity compared to the deoxycholate version. This allows clinicians to use the medication more effectively in high-risk patients.