Milbemycin from Streptomyces

S-Hydroxylation of milbemycins 54a-c, 16-membered ring macrolides isolated from Streptomyces hygroscopicus and showing potent and broad spectrum activity as anthelmintics, acaricides and insecticides, was found to be relatively efficient (yields around 50%) by selenium dioxide oxidation in formic acid and subsequent acidic hydrolysis (Scheme 6) [21]. 

Milbemycins, which were discovered by a Sankyo group, were isolated from Streptomyces hygroscopicus subspecies aureolacrimosus. Milbemycins exhibit exceptionally potent acaricidal and insecticidal activities. First, they were produced as a mixture of 13 components (tti-aio and Pi-ps) by fermentation of strain SANK 60,576 [236]. Furthermore, the mutant strain SANK 60,576 produced milbemycin D, E, F, G, and H in high yield [237]. 

On the other hand, an American Cyanamid group isolated milbemycin analogues, nemadectins a, [3, y, and X from Streptomyces cyaneogriseus sp. noncy-anogenus in 1987 [238]. The main congener, nemadectin a, is currently used as starting material for the production of commercial moxidectin used in veterinary medicine (Fig. 36). 

Increasing resistance towards anthelmintics has also become evident with various parasites. The need for a more ecologically rational pest management strategy has refocused attention on natural products. The discovery in 1979 of the potent anthelmintic and insecticidal activity of the aver-mectins and milbemycins (eg 1, 2), structurally related 16-membered macrocycles from Streptomyces species [4], has stimulated a search for other new and specific naturally occurring anthelmintics. 

Figure 1 Scanning electron micrograph of a novel Strepto-myces species from which compound (I) and many other related milbemycins have been isolated. (See Baker GH, Dorgan RJJ, Everett JR, Hood JD, and Poulton ME (1990) A novel series of milbemycin antibiotics from Streptomyces strain E225. II. Isolation, characterisation, structure elucidation and solution conformations. Journal of Antibiotics 43 1069-1076.)...

These are a family of novel macrolide antibiotics with high order of insecticidal and ascaricidal properties. The miibemycins are structurally related to the aver-mectins except for the fact that they have no substitution at position 13 and, therefore, may be called 13-deoxyavermectin aglycones. Originally nine miibemycins were isolated from the broth of Streptomyces hygroscopicus, subsp. aureolacrimosus [24,25]. Various other milbemycin derivatives were produced by fermentation of different strains of Streptomyces such as strain MA-5920 (prepared by fusion of S. aver-mitilis protoplast with S. hygroscopicus protoplast) [26], E-225 [27] and S. eurythermus [28]. The structure of the miibemycins is represented by the general formula 14 the important members of this class are milbemycin-D (15) and nemadectin (16) [29,30]. 

Milbemycin P3 (383) is a 16-membered macrocyclic lactone isolated from the fermentation broth of Streptomyces B-41-146 and is the simplest member of a family of compounds structurally related to the avermectins. Milbemycin P3 has been demonstrated to have marked insecticidal as well as limited antibiotic activity. Structurally, 383 is a 16-membered lactone fused to an aromatic ting. Although nearly devoid of asymmetric centers on the cyclic framework, it does contain the rather unusual spiroketal moiety. 

The discovery of milbemycins was first reported by researchers from Sankyo in 1974 [36, 37]. The original producing strain SANK 60576 was designated Streptomyces hygroscopicus subsp. aureolacrimosus [38]. The fermentation products from this Actinomycete and its mutants are many. Thirteen milbemycins were isolated from the original strain, they were named ol to aio and to [39]. Later, the ai component was named milbemycin A3, the as component milbemycin A4. More derivatives were isolated from mutant strains [40, 41], among them milbemycin D (Fig. 29.6.3). 

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