Amphotericin B Fungizone

Structural Formula Ball-and-Stick Model Space-filling Model

= Carbon = Hydrogen = Oxygen = Nitrogen

Amphotericin B, a "polyene" macrolide, is a naturally occurring molecule that is used for the treatment of severe systemic fungal infections.1 Such infections can be life-threatening especially in those whose immune system has been compromised by infection with AIDS, anticancer drugs, or immunosuppressive therapy. Fungal infections generally do not respond to antibiotics.

Fungi are eukaryotes that have a distinct cell nucleus containing proteins and DNA, as well as various cytoplasmic organelles such as the endoplasmatic reticulum, Golgi apparatus and mitochondria. The structure and biochemical machinery of fungal cells is very similar to that of mammalian cells. However, fungal and mammalian cells differ because fungi have rigid cell walls whereas mammalian cells do not. In addition, fungal membranes contain primarily ergosterol, whereas mammalian membranes contain cholesterol (see structures below).

Cholesterol Ergosterol

Polyene macrolides, first isolated in the early 1950s from soil microbes, proved to be a highly effective class of antifungal agents.2 More than 200 antifungal polyene macrolides have been discovered in the interim. Amphotericin B, isolated from Streptomyces nodosus in 1955, is a lactone with a 38-membered ring, a heptaene unit (blue), a hemiketal (green) and an aminosugar (red) unit as well as a hydroxyl-rich (polyol) region (highlighted in yellow above). The heptaene portion of seven double bonds in conjugation is hydrophobic, whereas the rest of the molecule is hydrophilic, rendering the molecule biphilic (amphiphilic). The heptaene part of amphotericin B interacts strongly with hydrophobic ergosterol within the fungal cell membrane. The hydrophilic polyol region of several amphotericin B molecules forms a channel in the membrane that allows the uncontrolled leakage of Na+, K+, and Ca2+ ions out of the fungus, eventually leading to cell death (see below; only two of 4-6 amphotericins in the aggregate are shown in the picture for clarity). Since amphotericin B has higher affinity for ergosterol than cholesterol, it preferentially binds to fungal cells. However, the dose of amphotericin B must be controlled because that selectivity is limited. There is a need for novel and potent antifungal drugs, since the incidence of severe systemic fungal infections in immunocompro-mized patients has increased and because drug resistance has emerged.

1. Int. J. Antimicrob Agents 2006, 27, S12-S16; 2. Curr. Med. Chem. 2003, 10, 211-223; Refs. p. 178

EXTRACELLULAR SPACE

amphotericin b k* k* ergosterol

ergosterol amphotericin b

Simplified picture of an ion channel formed from amphotericin B and ergosterol in a fungal membrane.

EXTRACELLULAR SPACE

amphotericin b k* k* ergosterol ergosterol amphotericin b

Simplified picture of an ion channel formed from amphotericin B and ergosterol in a fungal membrane.

PART IV. ANTIFUNGAL AGENTS

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