FK-506, a novel immunosuppressant isolated from a Streptomyces. I. Fermentation, isolation, and physico-chemical and biological characteristics.

Abstract

FK-506, a novel immunosuppressant, has been isolated from the fermentation broth of Streptomyces tsukuhaensis No. 9993 as colorless prism and the molecular formula was determined as C44H69NOi2«H2O. The compoundsuppressed immuneresponses in vitro and in vivo with mice. This immunosuppressiveeffect was more potent than that of ciclosporin.Ciclosporin (CS), a fungal metabolite, is an effective immunosuppressant with low myelotoxicity0 and has been used successfully as the primary drug to suppress the rejection of transplants.2"0It is now well established that CS inhibits the production of T cell-derived soluble mediators such as interleukin 2 (IL-2), interleukin 3 (IL-3) and gamma-interferon (IFN-f) induced by antigens and lectins.5~8) The immunosuppressive agent which would attack specific target sites of cell are expected to provide a useful prototype o drugs for immunotherapy. Accordingly, we hav< tested a wide range of fermented broths fo specific inhibitory effects on IL-2 production. As a result, a strain of Streptomyces tsukuba ensis No. 9993 was found to produce the poten immunosuppressive agent, designated by th< code number of FK-506. Taxonomic study or this strain will be presented in a separate paper.9) In this paper, we describe the fermentation, isolation procedures and some chemical and biological properties of FK-506. As shown in Fig. 1, FK-506 is a neutral macrolide. Determination of the chemical structure of FK-506 will be published elsewhere.10) Materials and MethodsFermentati on A seed medium 100 ml containing glycerol 1 %, corn starch 1 %, glucose 0.5%, cotton seed meal 1 %, corn steep liquor 0.5% and calcium carbonate 0.2% at pH 6.5 was poured into a 500-ml Erlenmeyer flask and sterilized at 120°C for 30 minutes. A loopful of slant culture of S. tsukubaensis No.

Stabilization of protein–protein interactions by small molecules

“…FK506 was isolated by scientists at Fujisawa Pharmaceuticals in 1984 as the active immunosuppressant component of a fermented broth from Streptomyces tsukubaensis [26]. FK506 is a 23-membered lactone belonging to the ascomycin macrolide class; it contains 14 asymmetric centers, nine sites of oxygenation and one amino acid, making targeted medicinal chemistry efforts a formidable challenge [27].…”

Efficacy and Safety of Topical Tacrolimus (0.03%) in the Treatment Localized Vitiligo

“…Tacrolimus acts on T cells and mast cells inhibiting T cell activation and the production of proinflammatory cytokines such as tumor necrosis factor (TNF) whose level are higher in vitiligo lesional skin. Moreover it prevents the release of proinflammatory mediators in mast cells by degranulation 18 .…”

“…The autoimmune theory remains the most widely accepted. Vitiligo has 18 from the fermentation broth of Japanese soil sample that contained the bacteria streptomyces tsukubaensis can be used as an alternative to topical steroids in many other forms of dermatitis. This ointment does not cause atrophy, telangectasiae or adverse ocular effects of topical corticosteroids which has limited application to the face and intertregnous areas 17 .…”

A utilização do tubo de ácido poliglicólico e FK506 na regeneração de nervos periféricos

“…Many substances have been assessed for peripheral nerves injuries treatment. Among those, the FK506 (Tacrolimus), an antibiotic isolated in 1984 for the bacteria Streptomyces tsukubaensis (14) .…”