Chemistry: molecular biology and microbiology – Micro-organism – tissue cell culture or enzyme using process... – Preparing oxygen-containing organic compound
Patent
1996-02-15
1998-03-10
Lankford, Jr., Leon B.
Chemistry: molecular biology and microbiology
Micro-organism, tissue cell culture or enzyme using process...
Preparing oxygen-containing organic compound
435195, 435196, 435197, 435911, C12N 914, C12N 916
Patent
active
057260494
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to a process for the conversion of pseudomonic acids and esters thereof to the corresponding monic acid.
Pseudomonic acids have well known antibacterial properties. Known pseudomonic acids include the tetrahydropyranyl compounds pseudomonic acid A (Nature, 1971, 234, 416; JCS Perkin Trans. I, 1977, 294), pseudomonic acid B (JCS Perkin Trans. I, 1982, 2827), pseudomonic acid C (JCS Perkin Trans. I 1982, 2827) and pseudomonic acid D (JCS Perkin Trans. I, 1983, 2655).
In particular, the present invention provides a process for the conversion of pseudomonic acid A (mupirocin) (I) ##STR1## to monic acid A (II) ##STR2## or the conversion of pseudomonic acid C (Ill) ##STR3## or its methyl ester to monic acid C (IV) ##STR4##
Monic acids are useful as a starting materials for producing biologically active compounds in particular pharmaceuticals. Beecham Group plc GB 1 587 058 describes the chemical preparation of monic acid. One problem with chemical methods of preparation has been that of extracting the product.
There is a requirement for an alternative to chemical hydrolysis of pseudomonic acids to monic acids. Although a large number of hydrolytic enzymes are known, surprisingly we have found that none of 60 or so commonly available animal, plant and microbial hydrolases (for example from Sigma Chemical Company, Poole, Dorset) tried to date have been found to have suitable activity. For example subtilisin E.C. 3.4.21.14 was found not to hydrolyse a 9-hydroxynonanoate ester from an analogue of pseudomonic acid A (Sime et al. 1987, Tet. Lett. 28(43), pp 5169-72).
Freer et al (Synthesis and Applications of Isotopically labelled compounds(1988), Proceedings 3rd International symposium, Elsevier) used a the required level of activity.
We have now found that enzymes suitable for use in the process of the invention can be derived from certain Actinomycetes in particular Kitasatosporia, Kibdelosporangium sp. and certain Streptomyces sp.
Accordingly, the present invention provides a process for the production of monic acids which comprises contacting the corresponding pseudomonic acid or an ester thereof with a hydrolase enzyme from a suitable microorganism.
By esters of pseudomonic acid we include those which are cleavable by the hydrolase enzyme of the invention to produce the corresponding monic acid. Suitable esters include (C1-C6) esters, particularly methyl esters.
The present invention also provides a method of screening for microorganisms capable of transforming pseudomonic acid into monic acid by incubating said organisms with pseudomonic acid and assaying for the loss of antibacterial activity compared to a pseudomonic acid standard.
Particularly suitable microorganisms include S. lividans in particular S. lividans NCIMB 11416, S. griseofuscsus ATCC 23916 and S. ambofaciens ATCC 23873 and Kibdelosporangium aridum ATCC 39922. The strain Kitasatosporia NCIMB 40568 is a novel microorganism and as such forms a further aspect of the present invention. This strain has been deposited at the National Collection of Industrial and Marine Bacteria (NCIMB), Aberdeen, Scotland under accession number NCIMB 40568 on 14 Jun. 1993.
Kitasatosporia sp. NCIMB 40568 is grey sporing and has the following characteristics: cell wall peptidoglycan: LL-A.sub.2 pm/meso- A.sub.2 pm Bacteriology!.
The medium for cultivating the microorganisms according to the invention suitably contains sources of assimilable carbon and nitrogen together with inorganic salts. Suitable sources of nitrogen include cornsteep liquor, yeast extract, soyabean flour, meat extract, cottonseed, flour, malt, distillers dried solubles, amino acids, protein hydrolysates and ammonium and nitrate nitrogen. Suitable carbon sources include glucose, lactose, maltose, starch, glycerol and treacle eg. Fowler's.
Suitably the culture medium also includes alkali metal ions (for example, sodium) halogen ions (for example chloride) and alkali earth metal ions (for example calcium and magnesium) as well as trace elements such as iron and cobalt
Suitab
REFERENCES:
patent: 4284570 (1981-08-01), Rogers et al.
Freer et al. Proceedings 3.sup.rd Intl. Symp., Elsevier, 1988 pp. 295-298.
Sime et al. Tet. Lett. Vol. 28(43) pp. 5169-5172 1987.
Mantle et al. Appl. Microbiol. Biotechnol. vol. 33, pp. 709-711 1990.
Hayes Esme Faith
Sime John Thomas
Woroniecki Stefan Roland
Yeandle David Alan
King William T.
Lankford , Jr. Leon B.
Lentz Edward T.
SmithKline Beecham p.l.c.
Tate Christopher R.
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