Polyenes

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Several structurally complex antifungal antibiotics have been isolated from soil bacteria of the genus Streptomyces. The compounds are similar, in that they contain a system of conjugated double bonds in macrocyclic lactone rings. They differ from the erythromycin-type structures (macrolides; see Chapter 8), in that they are larger and contain the conjugated -ene system of double bonds. Hence, they are called the poly-ene antibiotics. The clinically useful polyenes fall into two groupings on the basis of the size of the macrolide ring. The 26-membered-ring polyenes, such as natamycin (pimaricin), form one group, whereas the 38-membered macrocycles, such as amphotericin B and nystatin, form the other group. Also common to the polyenes are (a) a series of hydroxyl groups on the acid-derived portion of the ring and (b) a gly-cosidically linked deoxyaminohexose called mycosamine.The number of double bonds in the macrocyclic ring differs also. Natamycin, the smallest macrocycle, is a pentaene; nystatin is a hexaene; and amphotericin B is a heptaene.

The polyenes have no activity against bacteria, rickettsia, or viruses, but they are highly potent, broad-spectrum anti-fungal agents. They do have activity against certain protozoa, such as Leishmania spp. They are effective against pathogenic yeasts, molds, and dermatophytes. Low concentrations of the polyenes in vitro will inhibit Candida spp., Coccidioides immitis, Cryptococcus neoformans, H. capsu-latum, Blastomyces dermatitidis, Mucor mucedo, Aspergillus fumigatus, Cephalosporium spp., and Fusarium spp.

The use of the polyenes for the treatment of systemic infections is limited by the toxicities of the drugs, their low water solubilities, and their poor chemical stabilities. Amphotericin B, the only polyene useful for the treatment of serious systemic infections, must be solubilized with a detergent. The other polyenes are indicated only as topical agents for superficial fungal infections.

The mechanism of action of the polyenes has been studied in some detail. Because of their three-dimensional shape, a barrel-like nonpolar structure capped by a polar group (the sugar), they penetrate the fungal cell membrane, acting as "false membrane components," and bind closely with ergos-terol, causing membrane disruption, cessation of membrane enzyme activity, and loss of cellular constituents, especially potassium ions. In fact, the first observable in vitro reaction upon treating a fungal culture with amphotericin B is the loss of potassium ions. The drug is fungistatic at low concentrations and fungicidal at high concentrations. This suggests that at low concentrations, the polyenes bind to a membrane-bound enzyme component, such as an ATPase.

Amphotericin B

The isolation of amphotericin B (Fungizone) was reported in 1956 by Gold et al.29 The compound was purified from the fermentation beer of a soil culture of the actinomycete Streptomyces nodosus, which was isolated in Venezuela. The first isolate from the streptomycete was a separable mixture of two compounds, designated amphotericins A and B. In test cultures, compound B proved to be more active, and this is the one used clinically.30 The structure and absolute stereochemistry are as shown.

Amphotericin B is believed to interact with membrane sterols (ergosterol in fungi) to produce an aggregate that forms a transmembrane channel. Intermolecular hydrogen bonding interactions among hydroxyl, carboxyl, and amino groups stabilize the channel in its open form, destroying symport activity and allowing the cytoplasmic contents to leak out. The effect is similar with cholesterol. This explains the toxicity in human patients. As the name implies, amphotericin B is an amphoteric substance, with a primary amino group attached to the mycosamine ring and a carboxyl group on the macrocycle. The compound forms deep yellow crystals that are sparingly soluble in organic solvents but insoluble in water. Although amphotericin B forms salts with both acids and bases, the salts are only slightly soluble in water (—0.1 mg/mL) and, hence, cannot be used systemi-cally. To create a parenteral dosage form, amphotericin B is stabilized as a buffered colloidal dispersion in micelles with sodium deoxycholate.31 The barrel-like structure of the antibiotic develops interactive forces with the micellar components, creating a soluble dispersion. The preparation is light, heat, salt, and detergent sensitive.

Parenteral amphotericin B is indicated for the treatment of severe, potentially life-threatening fungal infections, including disseminated forms of coccidioidomycosis and histoplasmosis, sporotrichosis, North American blastomycosis, cryptococcosis, mucormycosis, and aspergillosis.

The usefulness of amphotericin B is limited by a high prevalence of adverse reactions. Nearly 80% of patients treated with amphotericin B develop nephrotoxicity. Fever, headache, anorexia, gastrointestinal distress, malaise, and muscle and joint pain are common. Pain at the site of injection and thrombophlebitis are frequent complications of intravenous administration. The drug must never be administered intramuscularly. The hemolytic activity of amphotericin B may be a consequence of its ability to leach cholesterol from erythrocyte cell membranes.

For fungal infections of the central nervous system (CNS) (e.g., cryptococcosis), amphotericin B is mixed with cerebrospinal fluid (CSF) that is obtained from a spinal tap.

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