Avermectins

The avermectins (Figure 3.67) are a group of macrolides with strong anthelmintic, insecticidal, and acaricidal properties, but with low toxicity to animals and humans. They are produced by cultures of Streptomyces avermectilis. Some eight closely related structures have been identified, with avermectins Bia and B2a being the most active antiparasitic compounds. Abamectin (a mixture of about 85% avermectin B1a and about 15% avermectin B1fo) is used on agricultural crops to control mites and insects. Ivermectin (Figure 3.67) is a semi-synthetic 22,23-dihydro derivative of avermectin B1a and was first used in veterinary practice against insects, ticks, mites, and roundworms. Although it is a broad spectrum nematocide against roundworms, it is inactive against tapeworms and flatworms, or against bacteria and fungi. It is an extremely potent agent, and is effective at very low dosages. It has now been introduced for use against filarial and several other worm parasites in humans. Avermectins act by blocking neuromuscular transmission in sensitive organisms by acting on GABA (y-aminobutyric acid) receptors.

(derived from isoleucine) at C-25, whilst the minor b component has an isopropyl group instead, e.g. avermectin B^. In this case, the starter group is 2-methylpropionyl-CoA, derived from the amino acid L-valine. The A-series of avermectins are the 5-methoxy analogues of the B-series.

Even larger macrolides are encountered in the polyene macrolides*, most of which have antifungal properties, but not antibacterial activity. The macrolide ring size ranges from 26 to 38 atoms, and this also accommodates a conjugated polyene of up to seven E double bonds. Relatively few methyl groups are attached to the ring, and thus malonyl-CoA is utilized more frequently than methylmalonyl-CoA as chain extender. Typical examples are amphotericin B (Figure 3.68) from Streptomyces nodosus and nystatin A1 from Strep-tomyces noursei. These have very similar structures and are derived from the same basic precursors (Figure 3.68). The ring size is contracted due to cross-linking by formation of a hemiketal. They have slightly different hydroxylation patterns, part of which is introduced by hydroxylation, and the two areas of conjugation in nystatin Ai are extended into a heptaene system in amphotericin B. Both compounds are glycosylated with the amino sugar D-mycosamine, and both are car-boxylic acids, a result of oxidation of a propionate-derived methyl group.

An unusual and clinically significant macrolide isolated from Streptomyces tsukubaensis is FK-506 (tacrolimus)* (Figure 3.69), which contains a

EnzS ,OH

u co2h CO2H

EnzS ,OH

co2h CO2H

Nystatin Amphotericin

CO2H

D-mycosamine amphotericin B

D-mycosamine nystatin Ai

D-mycosamine amphotericin B

D-mycosamine nystatin Ai

CO2H

Figure 3.68

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