著者

山下 道雄 松田 充功 大畑 暢敬 神田 宗和 檜垣 知臣

出版者

日本生物工学会

雑誌

生物工学会誌 : seibutsu-kogaku kaishi (ISSN:09193758)

巻号頁・発行日

vol.83, no.3, pp.123-131, 2005-03-25

参考文献数

3

被引用文献数

1

---

In 1989, in the course of our screening for new antifungal antibiotics with cell wall synthesis inhibition activity, FR901379 (WF11899A) was discovered in the culture broth of Coleophoma empetri F-11899. The strain was isolated from a soil sample collected in Iwaki city, Fukushima-prefecture, Japan. Because FR901379 had hemolytic activity, we decided to screen for semi-synthesis derivatives with low toxicity and high antifungal activity and evaluated many derivatives with substituted side chains. We started by using Actinoplanes utahensis to replace the palmitoyl group of FR901379 with other organic acids. After synthesizing several hundred organic acids and making repeated derivatives, we discovered FR131535, which had similar antifungal activity to FR901379 in vitro and in vivo and low hemolytic activity. It was not however selected as a development candidate because of insufficient antifungal activity. In the search for a more potent compound, we hypothesized that a compound with a similar molecular structure to FR131535 might produce a good antifungal drug. We therefore began the screening of Fujisawa's original acylase using a specially devised and effective screening system. After discovering "FR901379 Acylase" produced by Streptomyces sp. No. 6907, we continued with our evaluation of derivatives. We finally selected FK463 as a candidate compound for commercial drug development. In 1990, to establish an industrial manufacturing method for Micafungin (FK463), our laboratories (Fermentation Development Laboratories) commenced the following development research : (1) strain improvement of Coleophoma, (2) screening of "FR901379 Acylase"-producing strains, (3) studies to increase the scale of fermentation of FR901379 and "FR901379 Acylase", (4) determination of effective purification procedures for FR901379, a key intermediate of FR179642 and FK463, and (5) development of a HPLC assay system to measure the amount of objective compounds and impurities. Micafungin (general name, Trade mark : Funguard, Development No. : FK463) was launched in Japan on December 6, 2002. Approval in the USA and EU is pending and expected shortly.

著者

長尾 康次 上田 聡 神田 宗和 大畑 暢敬 山下 道雄 日野 資弘

出版者

公益社団法人 日本薬学会

雑誌

YAKUGAKU ZASSHI (ISSN:00316903)

巻号頁・発行日

vol.130, no.11, pp.1471-1478, 2010 (Released:2010-11-01)

参考文献数

10

被引用文献数

2 2

---

Natural fermentation products have long been studied as attractive targets for drug discovery due to their amazing diverse, complex chemical structures and biological activities. As such, a number of revolutionary drugs developed from natural fermentation products have contributed to global human health. To commercialize a drug derived from natural fermentation products, an effective chemical entity must be identified and thoroughly researched, and an effective manufacturing process to prepare a commercial supply must be developed. To construct such a manufacturing process for tacrolimus and micafungin, the following studies were conducted: first, we focused on controlling the production of the tacrolimus-related compound FR900525, a fermentation by-product of tacrolimus which was critical for quality assurance of the drug substance. FR900525 production was reduced by using a mutant strain which produced more pipecolic acid, the biosynthesis material of tacrolimus, than the original strain. Then, to optimize the fermentation process of FR901379, an intermediate of micafungin, a fed-batch culture was adopted to increase FR901379 productivity. Additionally, FULLZONETM impeller was installed into the scaled-up fermenter, reducing the agitation-induced damage to the mycelium. As a result, the mycelial form changed from filamentous to pellet-shaped, and the air uptake rate during fermentation was drastically improved. Finally, we conducted screening for FR901379 acylase-producing microorganisms, as FR901379 acylase is necessary to manufacture micafungin. We were able to easily discover FR901379 acylase-producing microorganisms in soil samples using our novel, convenient screening method, which involves comparing the difference in antibiotic activity between FR901379 and its deacylated product.