Polyene Antifungals

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The polyene antifungals are a group of macrocyclic lactones with a very large 26-38-membered ring. They are characterized by the presence of a series of conjugated E double bonds and are classified according to the longest conjugated chain present. Medicinally important ones include the heptaene amphotericin B, and the tetraene nystatin. There are relatively few methyl branches in the macrocyclic chain. The polyenes have no antibacterial activity but are useful antifungal agents. Their activity is a result of binding to sterols in the eukaryotic cell membrane, which action explains the lack of antibacterial activity because bacterial cells do not contain sterol components. Fungal cells are also attacked rather than mammalian cells, since the antibiotics bind much more strongly to ergosterol, the major fungal sterol (see page 253), than to cholesterol, the main animal sterol component (see page 236). This binding modifies the cell wall permeability and leads to formation of transmembrane pores allowing K+ ions, sugars, and proteins to be lost from the microorganism. Though binding to cholesterol is less than to ergosterol, it is responsible for the observed toxic side-effects of these agents on humans. The polyenes are relatively unstable, undergoing light-catalysed decomposition, and are effectively insoluble in water. This insolubility actually protects the antibiotic from gastric decomposition, allowing oral treatment of infections in the intestinal tract.

Amphotericin is an antifungal polyene produced by cultures of Streptomyces nodosus and contains principally the heptaene amphotericin B (Figure 3.68) together with structurally related compounds, e.g. the tetraene amphotericin A (about 10%), which is the 28,29-dihydro analogue of amphotericin B. Amphotericin A is much less active than amphotericin B. Amphotericin is active against most fungi and yeasts, but it is not absorbed from the gut, so oral administration is restricted to the treatment of intestinal candidiasis. It is administered intravenously for treating potentially life-threatening systemic fungal infections. However, it then becomes highly protein bound resulting in poor penetration and slow elimination from the body. After parenteral administration, toxic side-effects, including nephrotoxicity, are relatively common. Close supervision and monitoring of the patient is thus necessary, especially since the treatment may need to be prolonged. A liposome-encapsulated formulation of amphotericin has been shown to be much less toxic and may prove a significant advance. Candida infections in the mouth or on the skin may be treated with appropriate formulations.

Nystatin is a mixture of tetraene antifungals produced by cultures of Streptomyces noursei. The principal component is nystatin Ai (Figure 3.68), but the commercial material also contains nystatin A2 and A3, which have additional glycoside residues. Nystatin is too toxic for intravenous use, but has value for oral treatment of intestinal candidiasis, as lozenges for oral infections, and as creams for topical control of Candida species.

23-membered macrolactone that also incorporates an ^-heterocyclic ring. This compound is known to be derived from acetate and propionate, the fragments of which can readily be identified in the main chain. The starter unit is cyclohexanecar-boxylic acid, a reduction product from shikimate, and the piperidine ring and adjacent carbonyl are incorporated as pipecolic acid (see page 310) via an amide linkage on to the end of the growing chain. An unusual pentanoic acid unit is also incorporated to provide the propenyl side-chain. FK-506 is a particularly effective immunosuppressant, and is proving valuable in organ transplant surgery. Although rapamycin (sirolimus)* contains a very large 31-membered macrocycle, several portions of the structure are identical to those of FK-506. Cyclohexanecarboxylic acid and pipecolic acid are again utilized in its formation, whilst the rest of the skeleton is supplied by simple acetate and propi-onate residues (Figure 3.69).

Attracting considerable interest at the present time are the epothilones (Figure 3.70), a group of macrolides produced by cultures of the bacterium Sorangium cellulosum. These compounds employ an unusual starter unit containing a thi-azole ring, which is almost certainly constructed from the amino acid cysteine and an acetate unit (see also thiazole rings in bleomycin, page 42g). The macrolide ring also contains an extra methyl group at C-4, the result of methylation after or during polyketide chain assembly. The other interesting feature is that this bacterium produces epothilone A and epothilone B in the ratio of about 2:1. These compounds differ in the nature

CO2H CO2H CO2H V

cyclohexanecarbonyl-CoA (from shikimic acid)

propylmalonyl-CoA

pipecolic acid

propylmalonyl-CoA

pipecolic acid

Unusual Polyketide
tacrolimus (FK506)

OMe 1

OMe 1

OMe rapamycin (sirolimus)

OMe rapamycin (sirolimus)

Figure 3.69

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