Bafilolides, potent inhibitors of the motility and development of the free-living stages of parasitic nematodes

Three Streptomyces isolates were identified as producing macrolide antibiotics of the bafilomycin or leucanicidin types during an evaluation of Australian actinomyces for the production of inhibitors of larval development in the parasitic nernatode, Haemonchus contortus. Bafilomycins A₁, B₁, C₁, and D were obtained from culture A239 and the 2-O-methyl-l-rhamnosyl derivative of bafilomycin A₁, leucanicidin, from cultures A223 and A240. All these 'bafilolides' gave shuilar patterns of inhibition typified by an initial paralysis of newly hatched L₁ larvae and a lethal toxicity within 24 h. LD₅₀ values for inhibition of larval development of McMaster H. contortus ranged from 0.23 μg ml^-1 for leucanicidin to 2.5 μg ml^-1 for bafilomycin D. The bafilolides had broad spectrum nematocidal activity, being equi-potent as inhibitors of H. contortus, Trichostrongylus colubriformis and Ostertagia circumcincta larval development. Further, all bafilolides caused some inhibition of H. contortus L₃ motility, with the semi-synthetic analogue, bafilomycin B₂, the most potent inhibitor (LP₅₀ against McMaster H. contortus 1.9 μg ml^-1). Nematode strains resistant to the known benzimidazole, levamisole and avermectin anthelmintics showed no cross resistance to the bafilolides, supporting the hypothesis that the bafilolides act by an independent mechanism.