Avermectin from Streptomyces avermitilis

CD Denoya, RW Fedechko, EW Hafner, HAI McArthur, MR Morgenstern, DD Skinner, K Stutzman-Engwall, RG Wax, WC Wemau. A second branched-chain OC-keto acid dehydrogenase gene cluster (bkdFGH) from Streptomyces avermitilis. its relationship to avermectin biosynthesis and the construction of a bkdF mutant suitable for the production of novel antiparasitic avermectins. J Bacteriol 177 3504-3511, 1995. 

Several of the top 20 pharmaceuticals in gross sales in 1992 were natural products or close derivatives thereof (eg. Mevacor, Ceclor). Of the top 20 crop chemicals in this same period, only one class of compounds, the pyrethroids, are based on a natural substance, the plant metabolite pyrethrin. Three active areas of chemistry have the potential to impact this situation within the next ten years the methoxyacrylate family of fungicides based upon the fungal metabolite, strobilurin Basta, a post-emergent broad-spectrum herbicide based upon the Streptomyces viridochromogenes metabolite phosphinothricylalanylalanine and avermectin, and its semi-synthetic derivatives, insecticides originating from Streptomyces avermitilis. 

Ivermectin, a semisynthetic macrocyclic lactone, is a mixture of avermectin Bia and Bib- is derived from the soil actinomycete Streptomyces avermitilis. 

Eight naturally occurring, structurally related avermectins are produced by Streptomyces avermitilis [7], The avermectin polyketide structure is derived from seven acetate and five propionate residues, together with a single 2-methylbutyric acid or isobutyric acid residue which forms the sec-butyl or isopropyl group attached to the C25 of the spiroketal moiety [8,9] (Fig. 1). The avermectin agly-cone is further modified by glycosylation at C13, with the attachment of two O-methylated oleandrose residues and O-methylation at C5. Thus, S. avermitilis... 

Avermectins are a group of closely related compounds isolated from the fungus Streptomyces avermitilis that are used to control the parasites of humans and animals, as well as arthropod pests in crops. They have fairly high mammalian toxicity, but their movement into treated leaves, oral activity against insect pests, and rapid breakdown in sunlight are all favorable properties. In insects and worms poisoned by avermectin, inactivity and flaccid paralysis occur from its relaxing effect on muscles. 

Abamectin is an insecticide/acaricide that contains a mixture of avermectin Bja (>80%) and avermectin Bjb (<20%) as active ingredients. Avermectins, which are macrocyclic lactones, are derived from the actinomycete, Streptomyces avermitilis (soil microorganism). It is used to control insect and mite pests of a wide range of agronomic, fruit, vegetable, and ornamental crops. It is also used by home owners for control of fire ants. It has an oral LD50 in rats of 300 mg/kg. 

Ivermectins B1 are derived from the avermectines Bl, the natural fermentation products of Streptomyces avermitilis. The avermectins Bl have double bonds between carbon atoms at 22 and 23, whereas the ivermectins Bl have single bonds in these positions (Fig. 2a). They have an intermediate polarity. The ivermectins Bl are a mixture of two major homologs, ivermectins Bla (>80%) and ivermectins Bib (<20%), but a crude ivermectin complex also contains various minor components. Ivermectins Bl are broad-spectrum antiparasitic agents used against Onchocerca volvulus in human medicine and for food production animals such as cattle, swine, and horses. 

Chemical/Pharmaceutical/Other Class Avermectins are a group of chemically related natural and semisynthetic macrocyclic lactones (macrolide endectocides) produced from the fermentation products of Streptomyces avermitilis. The... 

The avermectins (AVM) are a family of naturally occurring macrolides which are produced by Streptomyces avermitilis and possess potent broad-spectrum anthelmintic, acaricidal and insecticidal activity (25-27). One of the major components of the avermectin complex is AVM Bla. This has been shown to interfere with neurotransmission at excitatory neuronal (nerve-nerve) synapses in the ventral nerve cord of A. suum where the mode of action seems to involve a GABA-ergic mechanism (1, 3) AVM Bla also abolishes the hyper polarizing potentials recorded from muscle bags of A. suum in response to stimulation of inhibitory motorneurones O, 3.). Kass and co-workers (2, 28) suggest that the effect on inhibitory neuromuscular transmission results from blockade of GABA receptors present on the postsynaptic muscle membrane. As the postsynaptic receptors are... 

In 1976 scientists at the Merck Corporation discovered a complex of eight closely related natural products, subsequently named avermectins A la through B2b, in a culture of Streptomyces avermitilis MA-4680 (NRRL8165) originating from a soil sample collected at Kawana, Ito City, Shizuoka Prefecture, Japan and isolated by the Kitasato Institute. Their structures are shown in Figure 1 (1—6). They are among the most potent anthelmintic, insecticidal, and acaricidal compounds known. 

One of the most successful attempts at generating a wide range of analogs of a natural product resulted from the isolation of a mutant of the avermectin-producing organism, Streptomyces avermitilis. Avermectins types a and b derive their C-25 substituents from isoleucme and valine, via incorporation of these compounds as coenzyme A derivatives of isobutync and 2-methylbutyric acids, respectively. This mutant lacked the functional branched-chain 2-oxo acid dehydrogenase activity and could not therefore incorporate these likely... 

Invermectin is usually extracted from the soil of actinomycete Streptomyces avermitilis, the natural avermectins are 16-membered macrocyclic lactones and is found to be a mixture of 22, 23-dihydro structural analogues of avermectins and B, prepared by catalytic hydrogenation (reduction). In reality, avermectins are members of a family of rather structurally complex antibiotics obtained by fermentative process with the pure isolated strain of S. avermitilis. An intensive screening of cultures for the anthelmintic drugs exclusively from the natural products ultimately gave birth to this wonderful drug. 

Extracted from the soil actinomycete Streptomyces avermitilis, the natural avermectins are 16-membered macrocyclic lactones that, on reduction of the C22-23 double bond, give rise to ivermectin (IVM), which is an 80 20 mixture of dihydroavermectin Bia and Bip, respectively. The natural avermectins have minimal biological activity, but IVM has proven to be quite beneficial in the treatment of various nematode infections. 

The naturally occurring avermectins are a group of 16-membered macrocyclic lactones, which are produced by fermentation from Actinomycetes from the genus Streptomyces (Fig. 29.6.1). The soil microorganism Streptomyces avermitilis MA-4860 (NRRL 8165) was first isolated at Merck Research Laboratories in 1976 from a soil sample of Japanese origin, collected by researchers of the Kitasato Institute [25]. From the fermentation, eight different avermectins were isolated, which consist of four pairs of homologues. Each parr contains a major component (the a-component) and a minor one (b-component), which are usually produced in a ratio between 80 20 and 90 10. 

Ivermectins B1 are broad-spectrum antiparasitic agents widely used for food-producing animals such as cattle, swine, and horse.They are derived from avermectins Bl, the natural fermentation products of Streptomyces avermitilis. 

In the middle of the 20th century, the synthetic development of DDT and other chlorinated hydrocarbons (C.H.), increased insecticidal activity well beyond that of most natural products. Problems arose with bioaccumulation of C.H. residues in the food chain, human fat tissue, mother s milk, as well as the development of insecticide resistance. It became obvious there were limitations to synthetic technology as well. The modification of a natural product, for example, from chrysanthemum flowers and their pyrethrum extracts (7) to pyrethroids such as allethrin, resmethrin, permethrin (2), and deltamethrin created a model in which insecticides are created from the skeleton of insecticidally active natural molecules. Thus, the avermectin, abamectin, ivermectin family of pesticides originated from compounds produced by the soil bacterium, Streptomyces avermitilis (5), and the commercially successful chloronicotinyl insecticides, though not derived from nicotine, are chemically related 4). Both pyrethroids and chloronicotinyls are currently used commercially as termiticides. We have previously provided a detailed review of natural products as pesticidal agents for control of the Formosan subterranean termites, Coptotermes formosanus Shiraki (5). 

The avermectins are a group of macrocyclic molecules (actually pentacyclic lactones) isolated from a fermentation broth of the soil organism Streptomyces avermitilis, and consist of eight major components with high anthelminthic. 

Stapley EO (1982) Avermectins, antiparasitic lactones produced by Streptomyces avermitilis isolated from a soil in Japan. In Umeza >ra H, Demain AL, Hata R, Hutchinson CR (eds) Trends in antibiotic research. Antibiotic Research Association, Tokyo, pp 154-170... 

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