Avermectins resistance

There is a need for development of new anthelmintics, as resistance in livestock has been recorded against benzimidazoles, imidothiazoles and the avermectin/macrocyclic lactones, in addition to older drugs... 

The avermectin natural products are pesticides possessing novel chemistry and mode of action. Cross-resistance has not been observed in laboratory or field studies with mites andinsects tolerant to commercially available organophosphate, carbamate, chlorinated hydrocarbon and pyrethroid pesticides. 

Yu and Nguyen (1996) showed that selection of a strain of diamondback moth (Plu-tella xylostella) with permethrin for 21 generations resulted in over 600-fold resistance to permethrin in this strain. The resistant strain was also cross-resistant to all pyrethroids tested, including bifenthrin, fenvalerate, esfenvalerate, A.-cyhalothrin, fluvalinate, and tral-omethrin. However, it remained susceptible to organophosphate, carbamate, cyclodiene, neonicotinoid, avermectin, and microbial insecticides tested. Biochemical studies indicated that pyrethroid resistance observed in this strain was most likely due to decreased target site sensitivity. 

Sangster N C 1999 Pharmacology of anthelmintic resistance in cyathostomes will it occur with the avermectin millbemycins. Veterinary Parasitology 85 189-204 Tarigo-Martinie J L, Wyatt A R, Kaplan R M 2001 Prevalence and clinical implications of anthelmintic resistance In cyathostomes in horses. Journal of the American Veterinary Medical Association 218 1957-1960 Taylor S M, Kenny J 1995 Comparison of moxidectin with ivermectin and pyrantel embonate for reduction of faecal egg count in horses. Veterinary Record 137 516-518 Uhlinger C 1990 Effects of three anthelmintic schedules on the incidence of coiic in horses. Equine Veterinary Journal 22 251-254... 

One additional effect of avermectin was observed in some muscle preparations, but never in the stretch receptor preparations. Concentrations of avermectin between 5 and 50 nM, which had no obvious effect on the membrane resistance, appeared to potentiate the effects of GABA. In these preparations, the application of GABA caused an apparently normal conductance increase, but the conductance remained high even after the GABA was washed away (the recovery from GABA treatment is normally very rapid). This conductance increase was reversed by picrotoxinin. 

In fact, only two new classes of insecticides have been developed for commercial use in the last 30 years. Both the synthetic pyrethroids and the avermectins have excellent mammalian saftety. However, both are encumbered by previously evolved target site resistance, selected by over-use of DDT and cyclodiene insecticides, respectively. Thus, the remaining importance of the OPs and the carbamates is obvious. 

One important group of insecticides, the avermectins, works differently by being agonists and not antagonists as the other, acting on the chloride channels. The avermectins are produced by Streptomyces avermitilies. The binding site is different, and cross-resistance to fipronil, the cyclodienes, and lindane does not seem to occur. The toxic symptoms in insects and mammals are different. Mammals poisoned with avermectins exhibit hyperexcitability, incoordination, and tremor followed by ataxia and paralysis. In insects and nematodes, the hyperexcitation phase is absent. Their symptoms are... 

Fritz, L. C., Wang, C. C., andGorio, A. (1979). Avermectin Bla irreversibly blocks postsynaptic potentials at the lobster neuromuscular junction by reducing muscle membrane resistance. Proc. Natl. Acad. Sci. USA. 76, 2052-2066. 

Neurotoxic antifeedants from Compositae should provide important leads into strategies that ameliorate the control of the Diabrotica complex. Phytochemicals with combined effects that result in loss of insecticide resistance, reduced feeding, decreased life span, and neurotoxicity in rootworms may be a practical avenue to low chemical input strategies for com production. Also, phytochemical antagonism of cyclodiene resistance may have important consequences to future control of com rootworm by insecticides such as avermectins and pyrethroids (e.g. tefluthrin) which, certainly in the former case (121) and at least secondarily in the latter case (122), act on the GABA gated-chloride ionophore complex. 

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). 

Avermectins offer some optimism since they are effective against insects resistant to other insecticides, and their differing mode of action mentioned above may prevent the development of cross-resistance (see also section 5.7). 

---