'Streptomyces tsukubaensis' was the first tacrolimus producer strain identified. Although it has been included in the Streptomyces genus, its taxonomic position has not been rigorously determined. By using a polyphasic approach, we have established that the tacrolimus producer strain 'S. tsukubaensis' NRRL 18488 represents a unique species in the Streptomyces genus, which is phylogenetically distant from other subsequently described producers. This fact means a horizontal transference of the tacrolimus-producing gene cluster. Physiology, nutrient requirement, and molecular genetics analyses of tacrolimus biosynthesis in 'S. tsukubaensis' necessitate chemically defined or semi-defined media, which work as a jigsaw puzzle and allow for pieces (nutrients) exchange. To date, studies related to 'S. tsukubaensis' have been mainly focused in the improvement of tacrolimus production using complex industrial fermentation media, which difficulty allows testing of tacrolimus overproduction enhancers or inhibitors because of the presence of non-defined substances. In the present work, two semi-defined media were developed in order to study the main factors involved in tacrolimus production in 'S. tsukubaensis'.
Two new indolocarbazole alkaloids, 4'-Af-methyl-5'-hydroxystaurosporine (2) and 5'-hydroxystaurosporine (3), were isolated together with the known staurosporine (1) from the culture broth of a marine Micromonospora sp. (strain L-31-CLCO-002). The fermentation, structural data and cytotoxic activities of these compounds against various tumorcell lines aregiven.
A novel bioactive macrolide, IB-96212 has been isolated from the fermentation broth of a marine actinomycete, L-25-ES25-008. The strain belongs to the genus Micromonospora. The macrolide showed a very strong cytotoxic activity against P-388, and lower but significant activity against A-549, HT-29, and MEL-28 cell lines. We describe the isolation, taxonomy and fermentation of the producing strain as well as the isolation ofIB-96212.A marine Micromonospora has been isolated from homogenates of a sponge. The strain has been found to produce a fermentation broth with cytotoxic activity. A new macrolide responsible for this activity has been isolated from this fermentation broth. Wedescribe in this paper the taxonomical characterization of the strain, its fermentation and the isolation of the active compound, together with the study of the in vitro activities. The structural elucidation is presented in an accompanyingpaper1}.
Materials and Methods
Mi cro organi sms
The number of tacrolimus (FK506)-producing isolates has increased remarkably because of the clinical importance of tacrolimus as an immunosuppressant. However, the taxonomy of several of these isolates has not been studied. The taxonomic status of strain ATCC 55098T , a tacrolimusproducing strain, was determined in this study. The genotypic, phenotypic and chemotaxonomic properties were consistent with the inclusion of strain ATCC 55098 T in the genus Streptomyces.
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