Avermectins activity

Ivermectin is the catalytic reduction product of avermectin, a macroHde containing a spiroketal ring system. Two other related antibiotics having significantly different stmctural features and biological properties, moxidectin and milbemycin oxime, were more recentiy introduced into the market. Although these compounds have no antimicrobial activity, they are sometimes referred to as antibiotics because they are derived from fermentation products and have very selective toxicities. They have potent activity against worms or helminths and certain ectoparasites such as mites and ticks. 

Table 2. Biological Activity of Abamectin (Avermectin B ) Against Mites and Insects ...

This area has been covered in a review by Eldefrawi and Eldefrawi [23]. The GABA -receptor channel is activated by GABA (Fig. 2), avermectin, muscimol, taurine (Fig. 2) and j -alanine (Fig. 2). The activation by agonists is potentiated by benzodiazepines and barbiturates. The channel is blocked by the competitive... 

Avermectins are a series of eight related natural products with potent anthelmintic and insecticidal activities produced by Gram-positive, filamentous soil bacteria Streptomyces avermitlis [30]. All of these molecules share a 16-membered macrocyclic PK aglycon with the attachment of a dimeric o-methyl-a-L-oleandrose to C-13 (Figure 13.6). Avermectins differ in three substituents R1 R2 and R3. Rj can be either a hydroxyl or hydrogen, in which case there is a double bond between the C-22 and C-23. R2 can be either methyl or ethyl, and R3 can be either hydrogen or methyl. 

In summary, a novel cyclohexyl avermectin analog B1 with enhanced antiparasitic activity was discovered and produced with high selectivity and excellent fermentation titer through deciphering biosynthesis, pathway engineering, and directed evolution. The new product, doramectin, is sold commercially as Dectomax. 

Hafner, E.W., Holley, B.W., Holdom, K.S. et al. (1991) Branched-chain fatty acid requirement for avermectin production by a mutant of Streptomyces avermitilis lacking branched-chain 2-oxo acid dehydrogenase activity. Journal of Antibiotics (Tokyo), 44, 349-356. 

The avermectins, a family of compounds with potent anthelmintic, insecticidal and acaricidal activity, have vividly demonstrated that fermentation products can have entirely unanticipated activities. Besides their utility in animals, they show great promise for the control of insect pests of plants. Although antibiotics have found only a limited role in the control of plant diseases, the desire to find environmentally acceptable alternatives to the chemicals currently used has prompted new research efforts to discover fermentation products for use as pesticides. 

The third milestone in the history of the use of fermentation products in agriculture was the discovery of the avermectins. They were first detected in an anthelmintic assay using mice infected with nematospiroides dubius (13). This is one of the few assays in which they could have been detected since they lack antibacterial and antifungal activity. 

Tests using helminth infections in a variety of laboratory animals soon revealed that the avermectins had activity against a variety of nematodes but lacked activity toward cestodes and trema-todes. During the course of testing in a number of other assays, they were found active against the flour beetle, Tribolium confusum (14). This activity against arthropods was confirmed in mice infected with larvae of the bot fly, Cuterebra fontinella. 

This dual activity against both nematode and arthropod parasites of animals was an unexpected bonus from a screen for anthelmintic agents. The reason for this broad activity lies in their mode of action. They act by interfering with y-aminobutyric acid (GABA) mediated neurotransmission. When treated with avermectin, the nematode Ascaris suum becomes paralyzed although it retains normal muscle tone (17). Picrotoxin, an antagonist of GABA, can reverse the effect of avermectin on neurotransmission vitro. 

The absence of GABA-mediated neurotransmission in cestodes and trema-todes explains the lack of activity of the avermectins against these organisms. 

Another incentive to this screening may have arisen from the discovery of two remarkably potent families of fermentation products with insecticidal and acaricidal activity, the milbemycins and the avermectins. Abamectin (a mixture of not less than 80% avermectin and not more than 20% avermectin is already... 

The avermectins were initially detected in a program in which thousands of microbial fermentation products were tested in mice for activity against the nematode, Nematospiroides dubius. 

The microorganism was classified as a new species of actinomycete. Streptomyces avermitilis. Its anthelmintic activity was shown to reside in 8 closely related macrocyclic lactones, named avermectins, which were also found to possess activity against free-living and parasitic arthropods. One of the natural components, avermectin is now being evaluated as a pesticide for the control of mites of citrus and cotton crops and control of the Red Imported Fire Ant. A chemical derivative, 22,23-dihydroavermectin or ivermectin, has been developed as an antiparasitic agent. It is being marketed for use in cattle, horses and sheep and is expected to become available for swine and dogs. 

Based on a correlation of anthelmintic activity and HPLC analysis of the total avermectin complex, it was estimated that the third fermentation contained a minimum of 9 pg/ml. Improvement of the medium increased the yield by the original culture (MA-4680) to 120 yg/ml. A high-producing isolate (MA-4848) obtained from this culture produced nearly 500 pg/ml of total avermectins. Thus, this culture yielded readily to medium improvement and isolate selection to produce relatively large amounts of the avermectins. Accounts of the early fermentation studies and taxonomy have been published (1-2). 

Results from these laboratory studies demonstrated that avermectin Bj had high toxicity for the twospotted spider mite (Tetranychus urticae) on bean plants. When applied in solution directly onto adult and nymphal spider mite populations on foliage, avermectin Bj was shown to be 50-200 times as potent as commercially available acaricides, with an LC q of 0.02-0.03 ppm. Additional tests on foliage with insects in the order Lepidoptera, Coleoptera, Homoptera, Orthoptera, Diptera, Isoptera and Hymenoptera confirmed the broad spectrum activity and potency of the avermectin family of compounds and avermectin Bj in particular. Table II provides LC q values for avermectin Bj for the control of larval forms of several of these insects in foliar residue assays (18). 

Table III. Activity of Avermectin Derivatives against Adult Gastrointestinal Helminths of Experimentally Infected Sheep on Oral Administration.

Avermectin and its derivatives are utilized for their antiparasitic activities in veterinary medicine. They also have anticonvulsant effects. Difluorinated analogues in positions... 

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