EP0368953A4 - Method and microorganism for the production of faeriefungin - Google Patents

Method and microorganism for the production of faeriefungin

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Publication number
EP0368953A4
EP0368953A4 EP19890904883 EP89904883A EP0368953A4 EP 0368953 A4 EP0368953 A4 EP 0368953A4 EP 19890904883 EP19890904883 EP 19890904883 EP 89904883 A EP89904883 A EP 89904883A EP 0368953 A4 EP0368953 A4 EP 0368953A4
Authority
EP
European Patent Office
Prior art keywords
carbonyl
faeriefungin
macrolide
pentaene
var
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Withdrawn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
EP19890904883
Other languages
English (en)
Other versions
EP0368953A1 (fr
Inventor
Alan R. Putnam
Saroj K. Mishra
Muraleedharan G. Nair
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.)
Michigan State University MSU
Original Assignee
Michigan State University MSU
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 Michigan State University MSU filed Critical Michigan State University MSU
Publication of EP0368953A1 publication Critical patent/EP0368953A1/fr
Publication of EP0368953A4 publication Critical patent/EP0368953A4/en
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D313/00—Heterocyclic compounds containing rings of more than six members having one oxygen atom as the only ring hetero atom
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N1/00—Microorganisms, e.g. protozoa; Compositions thereof; Processes of propagating, maintaining or preserving microorganisms or compositions thereof; Processes of preparing or isolating a composition containing a microorganism; Culture media therefor
    • C12N1/20—Bacteria; Culture media therefor
    • C12N1/205—Bacterial isolates
    • 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
    • C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
    • C12P17/02—Oxygen as only ring hetero atoms
    • C12P17/08—Oxygen as only ring hetero atoms containing a hetero ring of at least seven ring members, e.g. zearalenone, macrolide aglycons
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12R—INDEXING SCHEME ASSOCIATED WITH SUBCLASSES C12C - C12Q, RELATING TO MICROORGANISMS
    • C12R2001/00—Microorganisms ; Processes using microorganisms
    • C12R2001/01—Bacteria or Actinomycetales ; using bacteria or Actinomycetales
    • C12R2001/465—Streptomyces
    • C12R2001/545—Streptomyces griseus

Definitions

  • the present invention relates to a novel carbonyl pentaene macrolide composition, referred to as "faeriefungin", and the compounds contained therein as produced by a unique strain of Streptomyces which are antimicrobial, nematicidal and insecticidal.
  • the present invention relates to faeriefungin produced by Streptomyces griseus var. autotrophicus var. nov ATCC 53668.
  • the prior art has described carbonyl pentaene macrolide mixtures having the molecular formulae C 36 H 58 O 10 and C 37 H 60 O 10 which are stereoisomers of the faeriefungin of the present invention.
  • the prior art stereoisomeric forms have a limited ability to inhibit microorganisms, have significant cytotoxicity, and are unstable at room temperature.
  • mycoticin from Streptomyces ruber has been described by Burke, R. et al in Journal of Investigative Dermatology 23: 163-168 (1954). Mycoticin was active in vitro against yeasts and molds, was rapidly inactivated and relatively highly cytotoxic. It produced hemolysis in blood agar medium. The molecular and structural formulae for mycoticin were accurately determined much later by Wassermann, et al, J. of American Chemical Society 89, 6 (1967) and Wassermann, et al., Chemical Communications, 1634 (1970) and detailed analytical data was presented. The structural formulae were as follows :
  • R is H- or CH 3 - and referred to as "A” and "B", respectively. It is uncertain whether the pentaene macrolides being produced in the Wassermann et al studies were the same as those of Burke et al because of differences in the data.
  • Flavofungin is described by Bekesi, Nature, Vol. 181: 908 (1958). It was inactive against bacteria. Schneider, et al, Russian Journal (1967) compare related pentaene macrolide compositions. The mycoticin (mycothicin) from Streptomyces ruber is indicated to be a 1 to 1 mixture of A and B. Flavofungin is described as a 9:1 mixture of A to B. Antiviral activity is described. Vetlugiha, L. A., et al, Russian Journal (1974) set forth further analytical data including chromatographic spectra. Bognar et al, Tetrahedron Letters 7 , 471-474 (1970) concludes that mycoticin and flavofungin contain the same compounds in different proportions.
  • the ratio of A to B in flavofungin is set forth as 9:1.
  • Bognar et al., J.C.S. Perkin - I 1848 (1972) describe flavofungin and mycoticin. Analytical data is presented. Summaries of the properties of flavofungin and mycoticin are set forth in Antibiotics Vol. II Koryyoski et al, American Society for Microbiology (1978) and in Kirk-Othmer 3 , pages 21-47 (1978).
  • Objects It is an object of the present invention to provide a novel pentaene macrolide composition containing compounds having molecular formulae which are the same as flavofungin and mycoticin but with different stereoisomeric structures, stabilities and antimicrobial properties.
  • Figure 1 is a flow chart showing the method for isolation of faeriefungin using methanol (MeOH) or trichloromethane (CHCI 3 ).
  • Figure 2 shows an x-ray diffraction pattern for the novel pentaene macrolide composition of the present invention, referred to as faeriefungin (FUNGIN.RD), wherein the ratio of A to B by weight is about 1 to 1.
  • Figure 3 shows an x-ray diffraction pattern for the prior art mycoticin (MYCON.RD; MYC) wherein the ratio of A to B is 1 to 1.
  • MYCON.RD prior art mycoticin
  • the present invention relates to a carbonyl pentaene macrolide compound from a composition referred to as faeriefungin having a structural formula
  • R is selected from hydrogen (A) and methyl (B) and all double bonds are trans and having negative optical rotation and an x-ray diffraction pattern showing 28 crystalline peaks at a d-spacing between
  • the present invention relates to a carbonyl pentaene macrolide composition referred to as faeriefungin characterized by a melting point of 209-212oC with partial decomposition, by a molecular formulae selected from the group consisting of C 36 H 58 O 10 and C 37 H 60 O 10 and mixtures thereof and positive ion fast atom bombardment mass spectrometry indicated molecular ions of 651.4017 for C 36 H 59 O 10 and 665.4237 for C 37 H 61 O 10 , a negative optical rotation and an x-ray diffraction pattern as shown in Figure 1 for a 1 to 1 molar mixture.
  • the present invention relates to a composition which comprises Streptomyces griseus var. autotrophicus var. nov ATCC 53668 and a synthetic culture medium which maintains the Streptomyces griseus.
  • the present invention also relates to a method for producing a carbonyl pentaene macrolide referred to as faeriefungin which comprises growing Streptomyces griseus var. autotrophicus var. nov ATCC 53668 mycelia in an aqueous growth medium containing sources of carbon, nitrogen and inorganic substances to produce the carbonyl pentaene macrolide having a negative optical rotation pattern and an x-ray diffraction pattern as shown in Figure 1.
  • the present invention also relates to a method for inhibiting the growth of a microorganism which comprises exposing the microorganism to an effective amount of a carbonyl pentaene microlide compound from a composition referred to as faeriefungin having a structural formula:
  • R is selected from hydrogen (A) and methyl (B) and all double bonds are trans and having a negative optical rotation and an x-ray diffraction pattern with peaks at a d-spacing between 1.5408 and 43.9165 Angstroms for a 1 to 1 molar ratio of A to B.
  • the present invention relates to a mixed carbonyl pentaene macrolide composition referred to as faeriefungin for inhibiting the growth of microorganisms characterized by a melting point of 209-212°C with partial decomposition, by molecular formulae of C 36 H 58 O 10 and C 37 H 60 O 10 and mixtures thereof and fast atom bombardment mass spectrometry indicated molecular ions of 651.4017 for C 36 H 59 O 10 and 665.4237 for C 37 H 61 O 10 , by a negative optical rotation and by an x-ray diffraction pattern as shown in Figure 1 in a carrier in an amount between about 1 and 100 micrograms per ml or per gram.
  • faeriefungin for inhibiting the growth of microorganisms characterized by a melting point of 209-212°C with partial decomposition, by molecular formulae of C 36 H 58 O 10 and C 37 H 60 O 10 and mixtures thereof and fast atom bombardment mass spectrome
  • carrier means a pharmaceutically acceptable non-toxic substance that when mixed with the active ingredient or ingredients renders it suitable for administration.
  • the expression preferably excludes water and low-molecular weight organic solvents commonly used in chemical synthesis, except in the presence of other phramaceutically necessary ingredients such as salts in correct quantitites to render the composition isotonic, buffers, surfactants, coloring and flavoring agents, and preservatives.
  • suitable solid and liquid diluents and carriers are the following: water containing buffering agents which can be rendered isotonic by the addition of glucose or salts; non-toxic organic solvents; such as paraffins, vegetable oils; alcohols; glyc ⁇ ls; natural ground rock (for example kaolins, aluminas, talc or chalk); synthetic rock powders (for example highly dispersed silica or silicates); and sugars.
  • Oral administration can be effected utilizing solid and liquid dosage unit forms such as powders, tablets, dragees, capsules, granulates, suspensions, solutions and the like. Where appropriate, dosage unit formulations for oral administration can be microencapsulated to prolong or sustain the release as for example by coating or embedding particulate material in polymers, wax or the like.
  • Parenteral administration can be effected utilizing liquid dosage unit forms such as sterile solutions and suspensions intended for subcutaneous, intramuscular or intravenous injection. These are prepared by suspending or dissolving a measured amount of the compound in a nontoxic liquid vehicle suitable for injection such as an aqueous or oleaginous medium and sterilizing the suspension or solution. Stabilizers, preservatives and emulsifiers can also be added.
  • parenteral dosage will be from 0.01 to 50 mg/kg, preferably from 0.1 to 10 mg/kg, of body weight per day, and the oral dosage form will be from 0.1 to 500 mg/kg, preferably 0.5 to 100 mg/kg, of body weight per day.
  • Faeriefungin was isolated from the mycelium of Streptomyces griseus var. autotrophicus var. nov, ATCC 53668 (also known as MSU SM008). This strain was isolated from a soil sample collected from a fairy ring from a grass lawn. The composition was produced by growth in bacto peptone, glucose, Brer Rabbit-GreenTM Label-molasses, 5:10:20 grams per liter in distilled water (A-9 medium) under the following conditions. Smaller batches of cultures were grown in two liter baffle-bottomed Erlenmeyer flasks containing 400 ml medium, placed on a rotary shaker at 100-200 rpm at 26oC for 5 to 7 days.
  • ATCC 53668 was isolated from a soil sample collected from the center of a fairy ring. The soil was suspended in sterile physiological saline and serial dilutions were plated on various isolation media. The colony of this strain was picked up from a Czapeck agar plate (sucrose 20.0g, NaNO 3 3.0g, K 2 HPO 4 1.0g, MgSO 4 ⁇ 7H 2 O 0.5g, KCl 0.5g, FeSO 4 ⁇ 7H 2 O 0.01g, bacto agar 15.0g, distilled water 1 liter). The microorganism grows well at room temperature (25oC) on most of the laboratory media. On YMG agar (yeast extract, malt extract, glucose, agar; 4:10:4:18 grams per liter in distilled water), it produced slightly wrinkled colonies that were yellowish orange with abundant aerial hyphae at the periphery.
  • faeriefungin The isolation and purification of faeriefungin is as set forth in Figure 1.
  • the culture is grown in broth and then the cells are harvested.
  • the cells are treated with methanol and the broth is treated with trichloromethane.
  • the crystals (X'ls) of faeriefungin are separated by cooling from the methanol twice and then the filtrate is extracted with trichloromethane.
  • the crystals can be combined.
  • faeriefungin is both intra- and extra-cellular.
  • UV spectra of peracetate of faeriefungin has the
  • Faeriefungin acetate did not.
  • Mass Spectra Faeriefungin (homologous mixtures of C 36 H 58 O 10 and C 37 H 60 H 10 )
  • Faeriefungin was a mixture of 13, 15, 17, 19, 21, 23, 25, 27 octahydroxy-31-isopropyl-14, 30-dimethyl-hentriaconta -2,4,6,8,10, 28-hexen-31-olide (A) and 13, 15, 17, 21, 23, 25, 27 octahydroxy-14, 30-dimethyl-31-S-butyl hentriaconta-2,4,6,8,10,28-hexene-31-olide (B).
  • Faeriefungin is a 1:1 molar mixture of C 36 H 58 O 10 and C 37 H 60 O 10 .
  • Table 1 shows a comparison of the properties of faeriefungin, mycoticin and flavofungin.
  • Example 2 The specific rotations for the compositions produced by two Streptomyces strains, ATCC 3348 of Burke et al and Wassermann et al and ATCC 53668, in A-9 medium and the medium of Burke et al (1954) were determined.
  • the [ ⁇ ] 2 D 5 values were for a 0.2% solutions in pyridine and dioxane and 0.15% in MeOH. The results are shown in Table 2.
  • Flavofungin -85-90 - - - -47.51 -
  • FF Faerifungin, produced by ATCC 53668 in A-9 medium (1 to 1 A to B).
  • MYC-N Compound produced by ATCC 3348 in A-9 medium (9:1 A to B).
  • MYC Compound produced by ATCC 3348 in 'Burke's' medium (supposed to be mycoticin (1 to 1 A to B)).
  • MYC-N polyene macrolide
  • MF molecular formulae
  • the CD curves of the octa-acetate of mycoticin and flavofungin were similar in shape, but quantitatively different as shown in Table 3 (Bognar et al., and Brown et al., J. C. S. Perkin I, 1848, 1972).
  • the octa-acetyl faeriefungin produced a CD curve different from mycoticin and flavofungin octa-acetates. It is different both quantitatively and in shape.
  • Table 3(a) shows that faeriefungin and mycoticin N have different CD values. The results show that faeriefungin contains significantly different stereoisomers.
  • the structures are different from those characterized by Schreiber, S. L.
  • Peak Angle Tip width Peak Backg D spac I/Imax Type Qual no (deg) (deg) (cts) (cts) (Ang) (%) A1 A2 0t
  • Table 6 shows comparisons of minimum inhibitory concentrations (CMIC) of faeriefungin and other antifungal agents in ug/ml.
  • Example 6 In order to confirm the data from the literature, the cultures were grown in 500 ml baffled bottom Erlenmeyer flasks, each containing 100ml of the liquid A-9 medium. The inoculated flasks were placed on a rotary shaker at 200 r.p.m., 26°C. The pH and the antifungal activities were monitored daily up to a period of 14 days.
  • the antifungal activities were determined by spreading evenly a thick suspension (200 ⁇ 10 cells/ml) of the spores or yeast-like cells of the test species on Emmons (neopeptone, glucose, bacto agar; 10:20:18 grams per liter in distilled water) agar in 100 mm Petri dishes and placing 25 ul of the culture broth on the surface. The test culture was incubated at 26°C for 2 days. A clear zone of inhibition was indicative of antifungal activity. Production of the antifungal compound could be detected after 3 days, peaked on 8th day and declined after 11th day. During this period, pH of the medium ranged between 6 and 8. Larger batches were grown in 2 L flasks containing 400 ml of A-9 medium.
  • Faeriefungin was better than any of the three antibiotics tested. Faeriefungin also has a low MIC against a broad spectrum of fungi.
  • Table 7 shows the minimum inhibitory concentrations (MIC) in ug/ml of faeriefungin, amphotericin B and nystatin against various bacteria and fungi.
  • faeriefungin is active against a number of strains of bacteria whereas the prior art compositions are not.
  • Tables 8 and 9 show the reported activities for flavofungin and mycoticin.
  • Penicillium novum hybrid 8 Penicillium sp. (two strains) 10-20
  • Candida albicans (three strains) 4-5
  • Trichophyton rubrum (two strains) 10 Trichophyton. gypseum (two strains) 20 Trichophyton sulfureium 8
  • Organism mcg/ml, No. Hours on Agar
  • Cryptococcus neoformans ATCC 10226 6-8 Candida albicans ATCC 10261 6-10 Blastomyces dermatitidis ATCC 10225 2-4 Histoplasma capsulatum ATCC 10220 1-2 Sporotrichum schenckii ATCC 10213 1-3 Hormodendrum pedrosoi ATCC 9475 7-10 Coccidioides immitis Conant 2150 2-3
  • Streptococcus hemolyticus >100 Salmonella typhi >100 Leishmania donovani >100 Tryphanosoma tropica >100 Endamoeba histolytica >100
  • Table 10 shows a summary of the biological activity of faeriefungin, mycoticin and flavofungin.
  • Example 7 Table 11 shows the toxicity of the faeriefungin to human erythrocytes.
  • faeriefungin is non-toxic at low levels in vitro.
  • Broths of Streptomyces ATCC 53668 containing faeriefungin also showed a highly toxic rapid response (greater than 50% kill within 2 hours) on mosquito (Aedes aegypti) larvae.
  • pure mycoticin MYC-N was only moderately toxic to mosquito larvae (35% mortality at 100 ppm for 24 hours), possibly indicating that another component produced by ATCC 3348, may be the primary insecticidal moiety.
  • Broths were moderately toxic (rapid to slow) to cultures of the nematode Panagrellus redivivus.

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Abstract

Une composition de macrolide pentaène, appelée faeriefungin, et des composés qui la composent. On produit la composition par Streptomyces griseus var. Autotrophicus var. nov. Cette composition est utile pour inhiber la croissance de certains virus, bactéries et champignons ainsi que des nématodes et insectes.
EP19890904883 1988-04-05 1989-02-21 Method and microorganism for the production of faeriefungin Withdrawn EP0368953A4 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US17731188A 1988-04-05 1988-04-05
US177311 2002-06-21

Publications (2)

Publication Number Publication Date
EP0368953A1 EP0368953A1 (fr) 1990-05-23
EP0368953A4 true EP0368953A4 (en) 1991-09-11

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Family Applications (1)

Application Number Title Priority Date Filing Date
EP19890904883 Withdrawn EP0368953A4 (en) 1988-04-05 1989-02-21 Method and microorganism for the production of faeriefungin

Country Status (4)

Country Link
EP (1) EP0368953A4 (fr)
JP (1) JPH0699421B2 (fr)
CA (1) CA1337643C (fr)
WO (1) WO1989009770A1 (fr)

Family Cites Families (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2992162A (en) * 1952-09-09 1961-07-11 Rutgers Res And Educational Fo Candicidin and process of preparation
US3023204A (en) * 1956-05-07 1962-02-27 Parke Davis & Co Viridogrisein, and its fermentative production with griseoviridin
US2990330A (en) * 1957-06-06 1961-06-27 Gattani Mohan Lal Streptomyces griseus strain 528 nrrl 2607 antibiotic and fermentation process
US3057779A (en) * 1960-03-14 1962-10-09 American Cyanamid Co Antibiotic and production thereof
NL264634A (fr) * 1960-05-20
US3314853A (en) * 1964-08-25 1967-04-18 Squibb & Sons Inc Rubiflavin and a process for making same using streptomyces griseus
US4330624A (en) * 1980-12-03 1982-05-18 Merck & Co., Inc. Process for producing Tunicamycin
GB2093017B (en) * 1981-02-12 1985-08-21 Pirt Stanley John Polyene antibiotics

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, vol. 111, 1989, page 344, abstract no. 20568e, Columbus, Ohio, US; N. WANG et al.: "Fulongmycin, an antifungal antibiotic produced by Streptomyces strain B1829", & KANGSHENGSU 1988, 13(6), 402-7 *
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, vol. 89, no. 6, 1967, pages 1535-1536, Washington, US; H.H. WASSERMAN et al.: "The mycoticins, polyene macrolides from Streptomyces ruber" *
JOURNAL OF THE CHEMICAL SOCIETY, PERKIN I, vol. 14, 1972, pages 1848-1856, London, GB; R. BOGNAR et al.: "Flavofungin: A mixture of 13,15,17,19,21,23,25,27-octahydroxy-31-isopropyl-14-methyl- and 13,15,17,19,21,23,25,27-octahydroxy-14-methyl-31-s-butyl-hentriaconta-2,4,6,8,10,28-hexaen-31-olide" *
See also references of WO8909770A1 *

Also Published As

Publication number Publication date
EP0368953A1 (fr) 1990-05-23
JPH02503805A (ja) 1990-11-08
JPH0699421B2 (ja) 1994-12-07
WO1989009770A1 (fr) 1989-10-19
CA1337643C (fr) 1995-11-28

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