Amphotericin double bonds

Streptomyces nodosus produces natural products such as amphotericin A and B. These are macrocyclic (large-ring) compounds containing numerous (three to seven) double bonds and multiple hydroxyl groups which are usually located on one side of the molecule. Amphotericin B (9.103) and the very similar nystatin (9.104) are antifungal... 

Amphotericin is an amphoteric polyene macrolide (polyene = containing many double bonds macrolide = containing a large lactone ring of 12 or more atoms). It is nearly insoluble in water and is therefore prepared as a colloidal suspension of amphotericin and sodium desoxycholate for intravenous injection. Several new formulations have been developed in which amphotericin is packaged in a lipid-associated delivery system (Table 48-1 and Liposomal Amphotericin B). 

Polyene antibiotics, such as amphotericin B (II) which contains seven conjugated double bonds (heptaene moiety), are subject to attack by peroxyl radicals, leading to aggregation and loss of activity. ... 

Amphotericin is a fascinating molecule in that one half of the structure is made up of double bonds and is hydrophobic, while the other half contains a series of hydroxyl groups and is hydrophilic. It is a molecule of extremes and as such is ideally suited to act on the cell membrane in the way that it does. Several amphotericin molecules cluster together such that the alkene chains are to the exterior and interact favourably with the hydrophobic centre of the cell membrane. The tunnel resulting from this cluster is lined with the hydroxyl groups and so is hydrophilic, allowing the polar contents of the cell to escape (Fig. 2.6). 

The structure of nystatin (8) is closely related to that of amphotericin B (11) except that in the nystatin molecule the double bond system is interrupted by saturation of the bond separating the tetraene and diene chromophores. This would allow the bending of an otherwise rigid structure. A similar structure to that of the amphotericin B-sterol pores has been proposed for nystatin in sterol—lecithin bilayers [154,203,249]. The permeability characteristics of nystatin pores closely resembled amphotericin B pores and it was even possible to form mixed pores when nystatin was added to one side of the bilayer and amphotericin B to the other [209]. 

Pimaricin, also called natamycin, is a member of the family of polyene macrolides. These compounds consist of large macrolactone rings that have a characteristic series of conjugated double bonds, an exocyclic carboxyl group, and an unusual mycosamine sugar. In this chapter, we deal with pimaricin because this compound is the only one bearing an epoxy functionality. The other polyene macrolides such as nystatin, amphotericin, and candicidin will be treated in Sections 7.11.1 and 7.11.2. 

Starter units. The DH domain in AmphA is presumably inactive since it would not normally encounter a p-hydroxyacyl-ACP substrate. The AmphB protein contains the first two extension modules. As expected, these modules both contain mAT domains and reductive loops containing only KR domains. AmphC is a hexamodular protein that assembles most of the polyene unit of amphotericin. Modules 3-8 all contain a DH-KR reduction loop except module 5, which has a DH-ER-KR loop. The interdomain region preceding ER5 is 45 amino acids shorter than the NysC protein and has similar complete reduction loops in other PKS proteins. The shorter interdomain may restrict the movement of the amphotericin ER5 domain so that some nascent chains are transferred from ACP5 to KS6 before enoyl reduction takes place. This kinetic competition might explain why S. nodosus produces amphotericin B as well as amphotericin A in which the C-28—C-29 double bond is reduced. 

Polyenes. These antifimgal macrolides differ from antibacterial macrolides in the size of the lactone ring, ranging from 26 to 38 atoms, and with the presence of a series of conjugated double bonds. The only member systemically used is amphotericin B, produced by Streptomyces nodosus. Antifungal activity is due to interference with membrane sterols, resulting in permeability alteration (O Fig. 9.5). 

This polyene macroUde antibiotic is isolated from Strepto-tnyces nourseri and S. aMdus. Nystatin is considered too toxic for parenteral admirristration. It is composed of a number of tetraene compormds (compotmds that contain four conjugated double bonds), the principle component being nystatin Ai (Fig. 24.3) which has a very similar stmcture to amphotericin B. Its use is mainly reserved for the treatment of oral, perioral, intestinal, vulvovaginal or cutaneous Candida spp. infections. 

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