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EP1100947A1 - Production d'un antibiotique - Google Patents

Production d'un antibiotique

Info

Publication number
EP1100947A1
EP1100947A1 EP99938933A EP99938933A EP1100947A1 EP 1100947 A1 EP1100947 A1 EP 1100947A1 EP 99938933 A EP99938933 A EP 99938933A EP 99938933 A EP99938933 A EP 99938933A EP 1100947 A1 EP1100947 A1 EP 1100947A1
Authority
EP
European Patent Office
Prior art keywords
compound
proline
trace elements
production
amino acids
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP99938933A
Other languages
German (de)
English (en)
Other versions
EP1100947A4 (fr
Inventor
Neal C. Connors
Leslie A. Petersen
David L. Hughes
Lisa M. Dimichele
Thomas J. Novak
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Merck and Co Inc
Original Assignee
Merck and Co Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Merck and Co Inc filed Critical Merck and Co Inc
Publication of EP1100947A1 publication Critical patent/EP1100947A1/fr
Publication of EP1100947A4 publication Critical patent/EP1100947A4/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/50—Cyclic peptides containing at least one abnormal peptide link
    • C07K7/54—Cyclic peptides containing at least one abnormal peptide link with at least one abnormal peptide link in the ring
    • C07K7/56—Cyclic peptides containing at least one abnormal peptide link with at least one abnormal peptide link in the ring the cyclisation not occurring through 2,4-diamino-butanoic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P21/00—Preparation of peptides or proteins

Definitions

  • the fungus Glarea lozoyensis produces a family of structurally-related, pharmaceutically-important compounds known as the pneumocandins. These acylated hexapeptides are interesting in that all the constituent amino acids contain one or more hydroxyl groups.
  • Compound I is produced by cultivating the fungus Glarea lozoyensis (formerly identified as Zalerion arboricola) under aerobic conditions. A process for the production of Compound I is disclosed in U.S. Patent 5,194,377 which issued March 16, 1993. Compound I is produced by cultivating Glarea lozoyensis, ATCC No. 20868, deposited under the Budapest Treaty in the Culture Collection of the American Type Culture Collection at 12301 Parklawn Drive, Rockville, Md. 20852.
  • the present invention relates to an improved process for the production of Compound I of the formula
  • novel compounds which are structural analogues of Compound I produced during the fermentation of Compound I. These include compounds of the formula
  • Each of the compounds (II-XII) exhibits antifungal activity.
  • the invention also relates to the use of certain amino acids, trace elements and sugar content to enhance the production of Compound I and impact the production of certain analogue impurities.
  • the fungus Glarea lozoyensis (ATCC 74030) is used to produce Compound I and the structurally related analogues.
  • This improved production strain was derived ultimately from the wild-type organism, ATCC 20868, (isolated from a sample of fresh water) by sequential steps of N-methyl-N'-nitro-iV-nitrosoguanidme mutagenesis. The culture was maintained as aliquots of a mycelial suspension in 5% (v/v) glycerol stored at -70°C.
  • compositions of the seed and production media can be composed of a variety of carbon sources, nitrogen sources, inorganic salts, and trace nutrients in a variety of proportions. Where applicable these nutrients can be organic or inorganic, simple or complex. Each nutrient is present at a concentration appropriate and in proportion to the other nutrients in the medium. Typical useful seed and production media are listed below in Table 1 and Table 2.
  • a 250 ml Erlenmeyer flask containing 50 ml of LYCP-5 medium was inoculated aseptically with 1 ml of a thawed culture stock. This first stage seed culture was incubated at 25°C with 220 rpm agitation for 3-5 days. A 1 ml aliquot of the first stage seed was transferred to a second 250 ml Erlenmeyer flask containing 50 ml of LYCP-5 medium. This second stage seed culture was incubated as above for 3 days.
  • each treatment group For each variable tested (i.e., treatment group), several 250 ml Erlenmeyer flasks each containing 25 ml FGY medium or a variation thereof (described below) were inoculated at 5% (v/v) with second stage seed. The flasks were incubated at 25°C with 220 rpm agitation for 14 days. The pH for each treatment group was adjusted as required by removing one flask from the group, adding acid or base to return the pH to 5.0-5.5, and then adding this same volume of sterile titrant to the remaining flasks in the group. Where required, a volume of a sterile fructose solution was added during the fermentation to maintain the residual concentration within a specific range.
  • Amino acids such as glutamine, arginine, and ornithine which can be metabolized to ⁇ -pyrroline-5-carboxylate (P5C) also appear to have an impact on the analogues which are defined by the specific amino acid incorporated at the position "occupied” by 3-hydroxyproline in Compound I (Table 5).
  • Table 5 Effect of proline “related” amino acids added (5 gm/L) on or about day 6.
  • osmolarity can be controlled by maintaining the residual fructose concentration at high (>75 gm/L) or low ( ⁇ 30 gm/L).
  • the initial fructose concentration in the control process is 125 gm/L and is kept high by making two 50 gm/L additions during the 14 cycle.
  • the initial fructose concentration can be lowered to 40 gm/L and several 25 gm/L additions made during the course of the fermentation to maintain a low residual sugar level.
  • hydroxylation patterns of amino acids of Compound I are sensitive to zinc, cobalt and nickel. Additionally, amino acid additions to the production medium have a direct effect on the pneumocandins produced by the fermentation. Supplementation ofthe production medium with proline, trans-3- hydroxyproline and tr ⁇ «s-4-hydroxyproline effects the incorporation of trans-3 or tr ⁇ n.s-4-hydroxyproline residues in Compound I. The addition of threonine to the fermentation controls the level ofthe serine analogue, Compound IV.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Engineering & Computer Science (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Wood Science & Technology (AREA)
  • Zoology (AREA)
  • Biochemistry (AREA)
  • General Engineering & Computer Science (AREA)
  • Oncology (AREA)
  • Microbiology (AREA)
  • Biophysics (AREA)
  • Biotechnology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Communicable Diseases (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)

Abstract

Ce procédé est un perfectionnement à un procédé permettant de préparer le composé représenté par la formule générale (I). Le procédé de l'invention met en oeuvre certains acides aminés et certains cations divalents tels que le nickel, le cobalt et le zinc pour augmenter la teneur et pour diminuer la quantité d'analogues structuraux.
EP99938933A 1998-08-07 1999-08-04 Production d'un antibiotique Withdrawn EP1100947A4 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US9569198P 1998-08-07 1998-08-07
US95691P 1998-08-07
PCT/US1999/017444 WO2000008197A1 (fr) 1998-08-07 1999-08-04 Production d'un antibiotique

Publications (2)

Publication Number Publication Date
EP1100947A1 true EP1100947A1 (fr) 2001-05-23
EP1100947A4 EP1100947A4 (fr) 2001-09-05

Family

ID=22253174

Family Applications (1)

Application Number Title Priority Date Filing Date
EP99938933A Withdrawn EP1100947A4 (fr) 1998-08-07 1999-08-04 Production d'un antibiotique

Country Status (4)

Country Link
EP (1) EP1100947A4 (fr)
JP (1) JP2003510245A (fr)
AU (1) AU5331199A (fr)
WO (1) WO2000008197A1 (fr)

Families Citing this family (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6696412B1 (en) 2000-01-20 2004-02-24 Cubist Pharmaceuticals, Inc. High purity lipopeptides, Lipopeptide micelles and processes for preparing same
AU2002246688A1 (en) 2000-12-18 2002-07-30 Altus Biologics Inc. Methods for preparing purified daptomycin
KR20110011704A (ko) * 2008-06-25 2011-02-08 테바 기오기스제르갸르 자르트쾨렌 뮈쾨되 레스즈베니타르사사그 카스포펀진 불순물 ａ를 함유하지 않는 카스포펀진
CN101928670B (zh) 2009-09-24 2012-02-22 上海天伟生物制药有限公司 一种抗生素的高产菌株及其制备方法和用途
US8951958B2 (en) 2010-03-29 2015-02-10 Dsm Sinochem Pharmaceuticals Netherlands B.V. Purification of caspofungin intermediates
WO2013104576A1 (fr) 2012-01-13 2013-07-18 Dsm Sinochem Pharmaceuticals Netherlands B.V. Fermentation de cyclopeptides à une concentration augmentée en ions métalliques
CN112110991A (zh) * 2014-12-24 2020-12-22 上海天伟生物制药有限公司 一种含氮杂环六肽前体的组合物及其制备方法和用途
CN106755223A (zh) * 2017-01-20 2017-05-31 信泰制药（苏州）有限公司 一种纽莫康定b0的发酵方法
CN107201316B (zh) * 2017-07-14 2020-04-07 海正药业(杭州)有限公司 一种曲霉菌及其生产肺念菌素b0的方法
CN113046251B (zh) * 2019-12-27 2023-01-24 上海医药工业研究院 生产纽莫康定b0的基因工程菌、其制备方法及应用
CN113046250B (zh) * 2019-12-27 2023-01-24 上海医药工业研究院 生产纽莫康定b0的基因工程菌及其制备方法和应用

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4968608A (en) * 1987-10-07 1990-11-06 Merck & Co., Inc. Process for antifungal fermentation product
US4931352A (en) * 1987-10-07 1990-06-05 Merck & Co., Inc. Antifungal fermentation product
US5021341A (en) * 1990-03-12 1991-06-04 Merck & Co., Inc. Antibiotic agent produced by the cultivation of Zalerion microorganism in the presence of mannitol
US5049546A (en) * 1990-03-19 1991-09-17 Merck & Co., Inc. Antibiotic agents

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
No further relevant documents disclosed *
See also references of WO0008197A1 *

Also Published As

Publication number Publication date
WO2000008197A1 (fr) 2000-02-17
AU5331199A (en) 2000-02-28
JP2003510245A (ja) 2003-03-18
EP1100947A4 (fr) 2001-09-05

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