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Process to Increase the Production of Clavam

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Process to Increase the Production of Clavam Europäisches Patentamt *EP000832247B1* (19) European Patent Office Office européen des brevets (11) EP 0 832 247 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.7: C12N 15/54, C12P 17/18, of the grant of the patent: C12N 1/20 24.11.2004 Bulletin 2004/48 // (C12N1/20, C12R1:465) (21) Application number: 96921954.2 (86) International application number: PCT/EP1996/002497 (22) Date of filing: 06.06.1996 (87) International publication number: WO 1996/041886 (27.12.1996 Gazette 1996/56) (54) PROCESS TO INCREASE THE PRODUCTION OF CLAVAM ANTIBIOTICS VERFAHREN ZUR ERHÖHUNG DER PRODUKTION VON CLAVAM-ANTIBIOTIKA PROCEDE POUR AUGMENTER LA PRODUCTION D’ANTIBIOTIQUES CLAVAM (84) Designated Contracting States: (56) References cited: AT BE CH DE DK ES FI FR GB GR IE IT LI LU MC EP-A- 0 349 121 WO-A-94/18326 NL PT SE Designated Extension States: • FEMS MICROBIOLOGY LETTERS, vol. 110, 1993, SI pages 239-242, XP000601357 J.M.WARD AND J.E.HODGSON: "The biosynthetic genes for (30) Priority: 09.06.1995 GB 9511679 clavulanic acid and cephamycin production occur as a ’super-cluster’ in three (43) Date of publication of application: Streptomyces" cited in the application 01.04.1998 Bulletin 1998/14 • MICROBIOLOGY, vol. 140, no. 12, December 1994, pages 3367-3377, XP000601913 H.YU ET (73) Proprietors: AL.: "Possible involvement of the lat gene in the • SmithKline Beecham plc expression of the genes encoding ACV Brentford, Middlesex TW8 9GS (GB) synthetase (pcbAB) and isopenicillin N synthase • THE GOVERNORS OF THE UNIVERSITY OF (pcbC) in Streptomyces clavuligerus" cited in ALBERTA the application Edmonton, Alberta T6G 2E1 (CA) • MALMBERG ET AL: ’Precursor flux control through targeted chromosomal insertion of the (72) Inventors: lysine epsilon-aminotransferase (LAT) gene in • HOLMS, William, Henry Bioflux Limited Cephamycin C biosynthesis.’ JOURNAL OF 54 Dumbarton Road Glasgow G11 6AQ (GB) BACTERIOLOGY vol. 175, no. 21, November • PARADKAR, Ashish Sudhakar, 1993, pages 6916 - 6924 University of Alberta, • ROMERO J. ET AL: ’Isolation and biochemical Edmonton, Alberta T6G 2E1 (CA) characterization of Streptomyces-Clavuligerus • MOSHER, Roy Henry Universityof Alberta, mutants in the biosynthesis of clavulanic acid Edmonton Alberta T6G 2E1 (CA) and cephamycin C.’ APPLIED MICROBIOLOGY • Jensen, Susan E., Dr., Dept. of Biol. Sciences AND BIOTECHNOLOGY vol. 27, no. 5-6, 1988, Edmonton, Alberta T6G 2E9 (CA) pages 510 - 516 (74) Representative: White, Susan Mary GlaxoSmithKline Corporate Intellectual Property (CN9.25.1) 980 Great West Road Brentford, Middlesex TW8 9GS (GB) Note: Within nine months from the publication of the mention of the grant of the European patent, any person may give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall be filed in a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 0 832 247 B1 Printed by Jouve, 75001 PARIS (FR) 1 EP 0 832 247 B1 2 Description Microbiol. Lett. 110, 239-242] do not share common bi- osynthetic structural genes. Therefore there are no ap- [0001] The present invention relates to processes for parent biochemical links between the pathways. increasing the production of clavulanic acid and other [0008] Romero et al (1988) Appl. Microbiol. Biotech- clavams including those with strong β-lactamase inhib- 5 nol 27:510-516 describe a number of mutants of Strep- itory activity from producing organisms. The present in- tomyces clavuligerus and the effects of the mutations vention also provides novel organisms capable of pro- carried by these organisms on the biosynthesis of ce- ducing increased amounts of these clavams. phamycin C (a cephalosporin) and clavulanic acid. A [0002] Microorganisms, in particular Streptomyces number of these mutants were defective in enzymatic sp. produce a number of antibiotics including clavulanic 10 activities known to be essential for cephamycin C bio- acid and other clavams, cephalosporins, cephamycins, synthesis. For example the mutant strain ncc1 lacks LAT tunicamycin, holomycin and penicillins. There is consid- activity and also isopenicillin N synthetase (IPNS) activ- erable interest in being able to manipulate the absolute ity, both of which are absolutely required to synthesise and relative amounts of these antibiotics produced and cephamycin C. This mutant produced no cephamycin C accordingly there have been a large number of studies 15 and no clavulanic acid. However a mutant lacking IPNS investigating the metabolic and genetic mechanisms of alone, nce2, was found to retain the ability to produce these pathways [Domain, A.L. (1990) "Biosynthesis and clavulanic acid, at levels higher than that shown by the regulation of beta-lactam antibiotics. " In : 50 years of wild-type. Penicillin applications, history and trends]. Many of the [0009] Surprisingly we have found that when the LAT enzymes which carry out the various steps in the meta- 20 gene in the cephalosporin pathway of an organism is bolic pathways and the genes which code for these en- interfered with the amount of clavams produced by the zymes are known. organism is increased. [0003] In the cephalosporin metabolic pathway in, for [0010] Accordingly the present invention provides a example , Streptomyces clavuligerus three important process for increasing the amount of clavam produced antibiotics can be produced namely penicillin N, O-car- 25 by an organism having both a clavam pathway or a por- bamoyldeacetylcephalosporin C and cephamycin C. tion thereof and a cephalosporin pathway or a portion These antibiotics are synthesised from the tripeptide thereof by interfering with the conversion of L-lysine to precursor d-(L-a-aminoadipyl)-L-cysteinyl-D-valine L-α-aminoadipic acid in the cephalosporin pathway . (ACV) [J.F. Martin et al (1990)., "Clusters of genes in- [0011] Preferably the clavam has β-lactamase inhibi- volved in Penicillin and cephalosporin biosynthesis" In : 30 tory activity and more preferably the clavam is clavulanic 50 years of penicillin applications history and trends]. acid. [0004] The recognised first dedicated step in the bio- [0012] In a preferred aspect of the invention the proc- synthesis of both penicillins and cephalosporins in S. ess of conversion of L-lysine to L- α-aminoadipic acid is clavuligerus involves the enzyme lysine -ε - amino trans- interfered with by altering the function of the LAT en- ferase (LAT). The nucleotide sequence and derived 35 zyme or the lat gene. For example the enzyme can be amino acid sequence of S.clavuligerus lat gene is inhibited or otherwise blocked (for example by using a known [Tobin, M.B et al., (1991) J. Bacteriol, 173, non-metabolisable substrate or analog). 6223-6229]. [0013] Suitably the lat gene can be obtained by con- [0005] Malmberg et al (1993) J. Bacteriol. 175(21): ventional cloning methods (such as PCR) based on the p6916-6924 (and US patent 5,474,912 ( published 12 40 published sequence. The function of the gene can be December 1995)) describe a process for producing in- interfered with or eliminated/deleted by genetic tech- creased amounts of cephalosporins in S. clavuligerus niques such as gene disruption [Aidoo, K.A. et al., by inserting one or more copies of a LAT gene into the (1994), Gene, 147, 41-46], random mutagenesis, site chromosome of the organism. Although effects on β directed mutagenesis and antisense RNA. -lactam antibiotics are claimed, only effects on products 45 [0014] Mahro,B. and Demain, A (1987), Appl.Micro- of the cephalosporin pathway in S. clavuligerus are dis- biol. Technol.27, 272-275 described a spontaneous mu- closed ie. no effects on clavam production were meas- tant strain of S. clavuligerus (NP1) which did not pro- ured or described. duce cephamycin and was demonstrated to be defec- [0006] Clavulanic acid and other clavams are derived tive in lat, acvs and ipns enzyme activities. H. Yu et al from a 3 carbon compound [Townsend ,C.A. and Ho, M. 50 (1994) [Microbiology, 140,3367-3377] demonstrated F. (1985) J. Am. Chem. Soc. 107 (4), 1066-1068 and that the activity of these three enzymes can be recov- Elson, S. W and Oliver, R.S. (1978) J. Antibiotics XXXI ered by transforming the mutant with a fragment of DNA No.6, 568] and arginine [ Valentine , B.P et al (1993) J. encoding the entire lat gene (lat) and the upstream half Am Chem. Soc. 15, 1210-1211] . of the acvs gene (pcbAB). However there was no teach- [0007] The gene clusters which determine the biosyn- 55 ing of any effect in this mutant in relation to the produc- thesis of cephalosporins and clavulanic acid, although tion of clavulanic acid or other clavams. adjacent to each other on the S. clavuligerus chromo- [0015] In a further aspect of the invention there are some [Ward, J.M. and Hodgson, J.E (1993) FEMS provided plasmids containing a defective lat gene , pref- 2 3 EP 0 832 247 B1 4 erably the plasmids pCF002 and p486latap described EcoR1 and Kpn1 to liberate its 1.08 kb fragment insert. below. Suitably the plasmids are used to transform an The digest was fractionated by agarose gel electro- organism such as S. clavuligerus eg strain ATCC 27064 phoresis and the 1.08 kb fragment was eluted and ligat- (equivalent to S. clavuligerus NRRL 3585). ed to EcoR1 and Kpn1-digested pCF001A. The ligation [0016] In a further aspect of the invention there is pro- 5 mixture was used to transform MV1193 to apramycin re- vided an organism containing a defective lat gene. sistance. The resulting transformants were screened and a clone was isolated that contained a recombinant EXAMPLES plasmid pCF002 [see Fig 1(a)]which possessed the 1.08 kb 5'-lat fragment upstream of the 3'-lat fragment, [0017] In the examples all methods are as in Sam- 10 both in the same orientation, but separated from each brook, J., Fritsch, E.F.
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