Chemistry: molecular biology and microbiology – Micro-organism – tissue cell culture or enzyme using process... – Preparing compound containing saccharide radical
Patent
1996-01-05
1998-09-29
Marx, Irene
Chemistry: molecular biology and microbiology
Micro-organism, tissue cell culture or enzyme using process...
Preparing compound containing saccharide radical
4352521, 4351721, 4351722, 536 136, C12N 120
Patent
active
058144889
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
This invention relates to the fields of microbiology and antibiotics. Particularly, it relates to a new mutant strain, a method of its mutation breeding, to a monocomponent Gentamicin C.sub.1a produced by this strain and used as mother nucleus of semisynthetic antibiotic 1-N-ethylgentamicin C.sub.1a (1-N-Ethylgentamicin C.sub.1a being named Etimicin) to compositions composed of semisynthetic 1-N-ethylgentamicin derivatives as active component and pharmaceutically acceptable additives and their manufacturing methods.
BACKGROUND OF THE INVENTION
It is well known that there are three main components in Gentamicin (GM) which is produced by fermentation of present strains: Gentamicin C.sub.1 (GMC.sub.1), Gentamicin C.sub.2 (GMC.sub.2) and Gentamicin C.sub.1a (GMC.sub.1a). The quality as well as the effect of Gentamicin have direct relationship with the content of the three components. In ((Antibiotics)) Vol.7 No. 1 12.about.15, 1982, Mr. Yang Yun-liu et al. from the Academy of Sciences of China reported the Minimal Inhibitory Concentrations (MIC) against 74 strains of P.aeruginosa separated clinically and the values of LD.sub.50 to each component of gentamicin C. The component GMC.sub.1a was considered best. If a monocomponent gentamicin is to be separated and purified from multi-component gentamicin, complicated technology and equipments are required and the production cost is thus raised. In order to overcome these shortcomings, strains which produce a monocomponent gentamicin are needed. Gentamicin as a kind of aminoglycoside antibiotics was first found in 1963 by M. J. Weisten et al. of Schering Corporation of America, and it has been about twenty years since 1963 when it appeared on the market. Nowadays, gentamicin is still widely used clinically. But, because of its side-effects of ototoxicity and nephrotoxicity, the use of gentamicin is to some extent restricted in medical treatment. It is desired to develop a kind of novel gentamicin derivative that is of low toxicity and high efficiency, especially active against gentamicin-resistant strains.
In the research references, U.S. Pat. No. 4,230,847 discloses a compound of aminoglycoside antibiotics, a gentamicin derivative in which some amino groups of gentamicin are selectively protected. U.S. Pat. Nos. 4,063,015 and 4,044,123 disclose 1,3,2'-tri-N-acetylgentamicin which is an antibiotic and useful as an intermediate in the preparation of 6'-N-alkylaminoglycoside. Canadian Patent 1,034,573 discloses a method for preparing 1-N-replaced-4,6-diaminoglycosyl-1,3-diaminocyclitols. In the prior art, no one has found a strain which produces monocomponent gentamicin, and there is no report about the semisynthesic 1-N-ethylgentamicin derivatives and their compositions in which monocomponent gentamicin produced by fermentation of the strain is used as intermediate (mother nucleus).
DISCLOSURE OF THE INVENTION
The first object of this invention is to provide a strain by which monocomponent gentamicin can be produced. The said strain was deposited in the Centre of General Microorganisms Collection of China (abbreviated to CGMCC, address: Institute of Microbiology, Academia Sinica, Zhongguancun, Beijing 100090, P.R.China) on Apr. 23, 1993, and was accepted for deposit under the Budapest Treaty on the International Recognition of the Deposit of Microorganism for the purpose of Patent Procedure on Nov. 27, 1995. The strain is a M. echinospora mutant and its registration number is CGMCC0197.
The second object of this invention is to provide a method of mutation breeding by means of which the above strain can be obtained. The monospore suspension of Micromonospora echinospora, after exposure to UV for 3 min and 0.5% LiCl solution treatment for 30 min, is spread on a plate containing Micronomicin (2000 ug/ml), and cultured for 14 days at 37.degree. C. The monocolony is picked up and screened to obtain Micromonospora echinospora mutant CGMCC0197.
The third object of this invention is to provide a process for the ##STR1## Wherein:
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REFERENCES:
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patent: 4412068 (1983-10-01), Rosi
Y. Yun-liu et al., "Comparison of antibacterial activities of three C components of Gentamicin against p. aeruginosa strains", Antibiotics 7(1): 12-15 (1982).
Zhao et al., Kangshengsu (1984), 9(2), 94-8 (I).
Zhao et al., Zhongguo Kangshengsu Zazhi (1992), 17(1), 16-20 (II).
Wright et al., J. Chem Soc. Chem. Commun, (6). 206-208, 1976.
The Merck Index, Tenth Edition, p. 627.
Fan Jin
Fan Minqi
Hu Xiaoling
Liu Jun
Zhao Min
Jiansgu Institute of Microbiology
Marx Irene
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