Chemistry: molecular biology and microbiology – Micro-organism – tissue cell culture or enzyme using process... – Using a micro-organism to make a protein or polypeptide
Patent
1991-09-26
1993-06-29
Lilling, Herbert J.
Chemistry: molecular biology and microbiology
Micro-organism, tissue cell culture or enzyme using process...
Using a micro-organism to make a protein or polypeptide
435 74, 435 75, 4352521, 435803, 435822, 435867, C12P 2104, C12P 1944, C12R 129
Patent
active
052234134
DESCRIPTION:
BRIEF SUMMARY
The invention relates to a process for preparation of the vancomycin antibiotic in a microbiological way by an aerobic fermentation, by using an aminoglycoside-resistant mutant of a strain belonging to the Micropolyspora orientalis species on a culture-medium containing assimilable carbon and nitrogen sources as well as mineral salts.
Vancomycin is a glycopeptide-type antibiotic produced by strains belonging to the Micropolyspora orientalis species. In earlier systematic classifications these strains had been mentioned under the names Streptomyces orientalis and Nocardia orientalis, respectively [M. Goodfellow et al.: The Biology of Actinomycetes, Academic Press Inc. Ltd., London, page 129 (1984)]. This property of both of the above strains was first the described in U.S. Pat. No. 3,067,099.
For preparing vancomycin on an industrial scale, Micropolyspora orientalis microorganism is grown in a culture-medium containing assimilable carbon and nitrogen sources as well as mineral salts under aerobic conditions, then the antibiotic produced during the fermentation is separated from the fermentation broth (see e.g. U.S. Pat. Nos. 4,400,753 and 4,667,024).
It is known that the vancomycin antibiotic structurally consists of two essential moieties: a sugar unit, chemically .alpha.-O-vancosamine-.beta.-O-glucosyl and a heptapeptide unit which is a so-called pseudopeptide and not a genuine one. This distinction is important because in the microorganisms genuine peptides and proteins are synthetized on the surface of the so-called ribosomes, in a protein-synthetizing system being practically identical in all living organisms; whereas the pseudopeptide-type secondary metabolite products are produced not in the above system but on the surfaces of complex enzymes being independent from the ribosomes. The ribosomes, i.e. the "normal" protein-synthetizing systems of the cells are built up from ribosomal ribonucleic acids and proteins. It is also known that aminoglycoside-type antibiotics such as e.g. streptomycin, kanamycin, neomycin and gentamycin act on microorganisms sensitive to them in such a way that, being bound to specific sites of the ribosomal ribonucleic acids, they prevent the development of ribosomes having a structure necessary for the "normal" protein synthesis. In microorganisms, which are resistant to the aminoglycoside antibiotics, the structures of ribosomal ribonucleic acids building up the ribosomes are altered in such a manner that the binding of aminoglycosides is inhibited, whereby they cannot influence the ribosomal structure and become inactive.
Since the pseudopeptide-type secondary metabolic products are synthetized not on the ribosomes but on the surfaces of complex enzymes which are independent from the ribosomes and do not contain ribosomal ribonucleic acids, aminoglycoside-type antibiotics have substantially no effect on these enzymes. Indeed, no data or observations are found in the literature which would give any evidence of aminoglycoside-induced alteration of the non-ribosomal peptide or pseudopeptide synthesis.
The yields of known processes for the preparation of vancomycin are rather low.
Thus, it was aimed to develop a process resulting in a higher productivity in comparison to the earlier ones and to isolate novel strains for this purpose.
In the course of our inventigations the Micropolyspora orientalis NCAIM 001091 strain producing the vancomycin antibiotic was subjected to a mutagenic effect, then aminoglycoside-resistant mutants were isolated. The mutagenization was carried out according to the literature by using N-methyl-N'-nitro-N-nitrosoguanidine or UV irradiation as mutagenic agents. Other known mutagenic agents, e.g. radioactive irradiation or nitrogen mustards etc. may also be used.
It has surprisingly been observed after the mutagenic treatment that, among the streptomycin- and kanamycin-resistant colonies grown on a selective culture-medium containing streptomycin and kanamycin, a great number of colonies were found with a significantly higher vancomycin-producing capabi
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Andras Andrasi
Financsek Istvan
Garamvolgyi Mihaly
Jarai Miklos
Kegl Laszlo
Biochin Biotechnologial Leanyvallalat
Lilling Herbert J.
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