WO2004022767A1 - Solid state fermentation and fed batch for the production of an immunosuppressant - Google Patents

Solid state fermentation and fed batch for the production of an immunosuppressant Download PDF

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Publication number
WO2004022767A1
WO2004022767A1 PCT/IN2002/000185 IN0200185W WO2004022767A1 WO 2004022767 A1 WO2004022767 A1 WO 2004022767A1 IN 0200185 W IN0200185 W IN 0200185W WO 2004022767 A1 WO2004022767 A1 WO 2004022767A1
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Prior art keywords
fermentation
rice
solid substrate
wheat
compound
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PCT/IN2002/000185
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French (fr)
Inventor
Saurabh Garg
Ramakrishnan Melarkode
Ramavana Gururaja
Shrikumar Suryanarayan
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Biocon Limited
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Priority to PCT/IN2002/000185 priority Critical patent/WO2004022767A1/en
Priority to AU2002330737A priority patent/AU2002330737A1/en
Publication of WO2004022767A1 publication Critical patent/WO2004022767A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/18—Bridged systems
    • 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
    • C12P17/18—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms containing at least two hetero rings condensed among themselves or condensed with a common carbocyclic ring system, e.g. rifamycin
    • C12P17/188—Heterocyclic compound containing in the condensed system at least one hetero ring having nitrogen atoms and oxygen atoms as the only ring heteroatoms

Definitions

  • the present invention provides a novel method for producing compound of Formula I or its any salt form by solid state fermentation, of microorganisms of Streptomyces hygroscopicus capable of producing the compound of Formula I. BACKGROUND OF THE INVENTION
  • Rapamycin of formula I is a peptide isolated as an extract of the bacteria Streptomyces hygroscopicus and reported to have antifungal activity (British Patent 1436447). Subsequently rapamycin has been implicated as an immunosuppressant (Martel R.R. et al Can. J. Physiol. Pharmacol. 55, 48-51, 1977). The immunosuppressive effects of rapamycin have also been disclosed in FASEB 3, 3411 (1989). Rapamycin has been shown to be effective in inhibiting transplant rejection (U.S. patent application Ser. No. 362,544 filed Jun. 6, 1989).
  • Lipophilic antibiotics that inhibit the transcription of T cell activation genes and/or signal transduction pathways involved in T cell activation. This agent inhibits the proliferative response of lymphocytes to alloantigen stimulation, and a variety of T cell associated immune reaction.
  • the compound suppresses immune responses in vivo as well as in vitro and is more highly potent than cyclosporin. Studies reveal that as Rapamycin appear to cause fewer side effects than standard anti rejection treatment due to its novel mode of action, and thus the immunosuppressive action of Rapamycin is applicable in organ transplantation.
  • Rapamycin is a macrocyclic triene antibiotic produced by Streptomyces hygroscopicus, which was found to have antifungal activity, particularly against Candida albicans, both in vitro and in vivo [C. Vezina et al., J. Antibiot. 28, 721 (1975); S. N. Seghal et al., J. Antibiot. 28, 727 (1975); H. A. Baker et al., J. Antibiot. 31, 539 (1978); US 3,922,992; and US 3,993,749].
  • Rapamycin as a chemical compound producible by culturing a rapamycin-producing organism in an aqueous nutrient medium.
  • the compound has the property of adversely affecting the growth of fungi, for example, Candida albicans and Microsporum gypseum.
  • Rapamycin have been described in the literature (C. Vezina et al. J.
  • the present invention provides a novel method for production of compound of Formula I or its salts.
  • the invention provides a fermentation process in which the compound of Formula I or any of it's salt form, is produced on solid nutritious matrix.
  • the fermentation is also carried out in fed-batch mode to increase the productivity/yields of the final product.
  • the fermentation is carried out in a contained bio-reactor.
  • solid state fermentation or “solid state cultivation”, sometimes referred to as “semi-solid state fermentation” as used herein, means the process of fermenting microorganisms on a solid medium that provides anchorage points for the microorganisms in the absence of any freely flowing substance.
  • the amount of water in the solid medium can be any amount of water.
  • the solid medium could be almost dry, or it could be slushy.
  • solid state fermentation and “semi-solid state fermentation” are interchangeable.
  • fed-batch fermentation or "fed-batch technique”.
  • fed-batch fermentation means a fermentation process carried out where substrate or nutrients are added in small increments as the fermentation progresses.
  • the substrate or nutrient is added in small increments that would encourage the production of secondary metabolites, because some secondary metabolite production is inhibited by high concentrations of substrate or substrates, so this method would encourage the production of such metabolites.
  • Supplement of nutrients at a time when the initially fed nutrient are consumed by the microorganisms or culture also help in providing more energy to the microorganism which in turn increases the overall production of the secondary metabolites.
  • Bioreactor means a device capable of holding fermentation media inoculated with microorganism and carrying out the process of solid state fermentation in a contained manner.
  • a bioreactor can be used to grow any microorganism capable of growing under specified conditions in a contained environment.
  • Some examples of microorganisms capable of growing in a bioreactor are fungi, yeast and bacteria.
  • the present invention discloses a process for production of compound of Formula I or its any salt form, by culturing a microorganism capable of producing such compound on solid nutrient matrix wherein, optionally the nutrients are fed in adequate quantities during the growth of the culture so that the production of the product increases significantly.
  • the instant invention discloses a process for the manufacture of compound of Formula I and its salts by solid substrate fermentation.
  • the solid substrate fermentation is carried out using Streptomyces hygroscopicus.
  • the solid substrate for fermentation is selected from wheat bran, wheat rawa, oat meal, broken wheat, boiled rice, rice bran, rice rawa, beaten rice, maize bran, maize grits, oat bran, bagasse, tapioca residue, soy grits, soy flakes, rice flakes, ceramic beads, glass beads, sponge or a mixture of two or more of these.
  • the solid substrate fermentation is a fed-batch fermentation.
  • the feeding for fed-batch fermentation is done at the beginning of the fermentation or at intervals throughout the fermentation.
  • the carbon source for feeding is selected from glucose, sucrose, starch (maize, wheat, tapioca, potato), modified starch, maltose, malto- dextrin, soybean oil, acetate or a mixture of two or more of these.
  • the nitrogen source for feeding is selected from ammonium sulphate, dried yeast, ammonium nitrate, sodium nitrate, bacteriological peptone, yeast extract, casein hydrolyzate, soy peptone, soy flour, cotton seed flour, corn steep liquor or a mixture of two or more of these.
  • the first aspect of the invention is production of compound of Formula I or its any salt form.
  • the compound is afforded by culturing Streptomyces hygroscopicus on solid nutrient matrix e.g. wheat bran, wheat rawa, broken wheat, boiled rice, rice bran, rice rawa, beaten rice, rice flakes, maize bran, maize grits, oat bran, bagasse, tapioca residue, soy grits, soy flakes, ceramic beads, glass beads, sponge or a mixture of one or more of these.
  • the product is then purified by conventional techniques comprising filtration, centrifugation, chromatography, extraction, distillation, concentration, precipitation, crystallization and drying.
  • the second aspect of invention is production of compound of
  • Formula I or its any salt form The compound is afforded by culturing Streptomyces hygroscopicus on solid nutrient matrix e.g. wheat bran, oatmeal, soybean meal, wheat flour, soybean flakes, maize bran etc. The culture is then fed with nutrients to increase production of the final product.
  • the product is purified by conventional techniques comprising filtration, centrifugation, chromatography, extraction, distillation, concentration, precipitation, crystallization and drying.
  • Solid state fermentation lOgm each of wheat bran, maize flakes, wheat rawa, rice rawa, oat meal, maize bran, rice bran, were taken in separate petri plates. Adequate amount of water was added and sterilized at 121 deg C for 30 minutes. 10 ml inoculum from 4 day old seed meclium was added. The entire substrate was mixed properly with the inoculum and incubated at 28 deg C for 7 days. Following results were obtained.
  • Example 2 Solid state fermentation was conducted as in Example 1 using 75 g ceramic beads as the solid support in a petri-plate, 15 mL of. Streptomyces hygroscopicus inoculum grown in seed medium was added. The result obtained is given in the table below.
  • Example 2 Solid state fermentation was conducted as in Example 1 using different solid supports in combination. lOgm of this substrate is taken in petri plate and 10ml of Streptomyces hygroscopicus inoculum grown in seed medium was added. The results obtained are given in the table below.
  • Solid state fermentation was conducted as in Example 3 using a mixture of wheat bran, wheat rawa and oat meal. lOgm of this substrate is taken in petri plate and 10ml of Streptomyces hygroscopicus inoculum grown in seed medium was added along with a liquid nutrient feed consisting of glucose and dried yeast. The feed was added every alternate day up to 4 th day.
  • Seed inoculum of Streptomyces hygroscopicus is obtained as explained in Example 1. 3.5L of this inoculum was used for inoculating 35 L of the same seed medium taken in a 50L fermenter. This is grown for 48 hr at 28°C. This is used as an inoculum for solid state fermentation. 15 kg of substrate mixture consisting of wheat bran, wheat rawa and oat meal was loaded into a bioreactor having 22600 cm 2 surface area. The bioreactor was sterilised at 121 deg C for 1 to 2 hours using steam. After the sterilization the temperature of the solid substrate was brought down to 28 deg C. 15 L of the above inoculum was added to the solid substrate along with 2 L of glucose and dried yeast feed and mixed.

Abstract

The present invention provides a novel method for producing compound of Formula (I) or any of its salt form, by solid state fermentation, optionally using fed-batch technique by culturing microorganisms capable of producing the compound of Formula (I).

Description

SOLID STATE FERMENTATION AND FED BATCH FOR THE PRODUCTION OF AN -IMMUNOSUPPRESSANT BACKGROUND OF INVENTION
The present invention provides a novel method for producing compound of Formula I or its any salt form by solid state fermentation, of microorganisms of Streptomyces hygroscopicus capable of producing the compound of Formula I. BACKGROUND OF THE INVENTION
Rapamycin of formula I is a peptide isolated as an extract of the bacteria Streptomyces hygroscopicus and reported to have antifungal activity (British Patent 1436447). Subsequently rapamycin has been implicated as an immunosuppressant (Martel R.R. et al Can. J. Physiol. Pharmacol. 55, 48-51, 1977). The immunosuppressive effects of rapamycin have also been disclosed in FASEB 3, 3411 (1989). Rapamycin has been shown to be effective in inhibiting transplant rejection (U.S. patent application Ser. No. 362,544 filed Jun. 6, 1989).
They are lipophilic antibiotics that inhibit the transcription of T cell activation genes and/or signal transduction pathways involved in T cell activation. This agent inhibits the proliferative response of lymphocytes to alloantigen stimulation, and a variety of T cell associated immune reaction. The compound suppresses immune responses in vivo as well as in vitro and is more highly potent than cyclosporin. Studies reveal that as Rapamycin appear to cause fewer side effects than standard anti rejection treatment due to its novel mode of action, and thus the immunosuppressive action of Rapamycin is applicable in organ transplantation.
Figure imgf000003_0001
Rapamycin is a macrocyclic triene antibiotic produced by Streptomyces hygroscopicus, which was found to have antifungal activity, particularly against Candida albicans, both in vitro and in vivo [C. Vezina et al., J. Antibiot. 28, 721 (1975); S. N. Seghal et al., J. Antibiot. 28, 727 (1975); H. A. Baker et al., J. Antibiot. 31, 539 (1978); US 3,922,992; and US 3,993,749].
U.S. Pat. No. 3,929,992 to Ayerst discloses the macrolide compound rapamycin and its antibiotic and antifungal properties. Recent publications, (see J. of Immunology Vol. 144, p. 251-258 (No. 1>, Jan. 1990 by F. J. Dumont et. al.,) disclose the use of the compound additionally as an immunosuppressant.
US 3,993,749 disclose Rapamycin as a chemical compound producible by culturing a rapamycin-producing organism in an aqueous nutrient medium. The compound has the property of adversely affecting the growth of fungi, for example, Candida albicans and Microsporum gypseum.
Fermentation and purification of Rapamycin and 30-demethoxy
Rapamycin have been described in the literature (C. Vezina et al. J.
Antibiot. (Tokyo), 1975, 28 (10), 721; S. N. Sehgal et al, J. Antibiot. (Tokyo), 1975, 28(10), 727; 1983, 36(4), 351; N. L. Pavia et al., J. Natural
Products, 1991, 54(1), 167-177).
The prior art literature does not disclose production of compound of
Formula I or any of its salt form, by solid substrate fermentation or solid state fermentation with fed-batch technique. SUMMARY OF THE INVENTION
The present invention provides a novel method for production of compound of Formula I or its salts.
In preferred embodiments, the invention provides a fermentation process in which the compound of Formula I or any of it's salt form, is produced on solid nutritious matrix. The fermentation is also carried out in fed-batch mode to increase the productivity/yields of the final product. The fermentation is carried out in a contained bio-reactor.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
Definitions "Solid state fermentation" or "solid state cultivation": The term
"solid state fermentation" or "solid state cultivation", sometimes referred to as "semi-solid state fermentation" as used herein, means the process of fermenting microorganisms on a solid medium that provides anchorage points for the microorganisms in the absence of any freely flowing substance. The amount of water in the solid medium can be any amount of water. For example, the solid medium could be almost dry, or it could be slushy. A person skilled in the art knows that the terms "solid state fermentation" and "semi-solid state fermentation" are interchangeable.
"Fed-batch fermentation" or "fed-batch technique". The term fed-batch fermentation as used herein, means a fermentation process carried out where substrate or nutrients are added in small increments as the fermentation progresses. The substrate or nutrient is added in small increments that would encourage the production of secondary metabolites, because some secondary metabolite production is inhibited by high concentrations of substrate or substrates, so this method would encourage the production of such metabolites. Supplement of nutrients at a time when the initially fed nutrient are consumed by the microorganisms or culture also help in providing more energy to the microorganism which in turn increases the overall production of the secondary metabolites. "Bioreactor": The term "bioreactor" as used herein, means a device capable of holding fermentation media inoculated with microorganism and carrying out the process of solid state fermentation in a contained manner. A bioreactor can be used to grow any microorganism capable of growing under specified conditions in a contained environment. Some examples of microorganisms capable of growing in a bioreactor are fungi, yeast and bacteria.
The present invention discloses a process for production of compound of Formula I or its any salt form, by culturing a microorganism capable of producing such compound on solid nutrient matrix wherein, optionally the nutrients are fed in adequate quantities during the growth of the culture so that the production of the product increases significantly. The instant invention discloses a process for the manufacture of compound of Formula I and its salts by solid substrate fermentation.
The solid substrate fermentation is carried out using Streptomyces hygroscopicus.
The solid substrate for fermentation is selected from wheat bran, wheat rawa, oat meal, broken wheat, boiled rice, rice bran, rice rawa, beaten rice, maize bran, maize grits, oat bran, bagasse, tapioca residue, soy grits, soy flakes, rice flakes, ceramic beads, glass beads, sponge or a mixture of two or more of these.
The solid substrate fermentation is a fed-batch fermentation. The feeding for fed-batch fermentation is done at the beginning of the fermentation or at intervals throughout the fermentation.
The carbon source for feeding is selected from glucose, sucrose, starch (maize, wheat, tapioca, potato), modified starch, maltose, malto- dextrin, soybean oil, acetate or a mixture of two or more of these.
The nitrogen source for feeding is selected from ammonium sulphate, dried yeast, ammonium nitrate, sodium nitrate, bacteriological peptone, yeast extract, casein hydrolyzate, soy peptone, soy flour, cotton seed flour, corn steep liquor or a mixture of two or more of these.
The first aspect of the invention is production of compound of Formula I or its any salt form. The compound is afforded by culturing Streptomyces hygroscopicus on solid nutrient matrix e.g. wheat bran, wheat rawa, broken wheat, boiled rice, rice bran, rice rawa, beaten rice, rice flakes, maize bran, maize grits, oat bran, bagasse, tapioca residue, soy grits, soy flakes, ceramic beads, glass beads, sponge or a mixture of one or more of these. The product is then purified by conventional techniques comprising filtration, centrifugation, chromatography, extraction, distillation, concentration, precipitation, crystallization and drying.
The second aspect of invention is production of compound of
Formula I or its any salt form. The compound is afforded by culturing Streptomyces hygroscopicus on solid nutrient matrix e.g. wheat bran, oatmeal, soybean meal, wheat flour, soybean flakes, maize bran etc. The culture is then fed with nutrients to increase production of the final product. The product is purified by conventional techniques comprising filtration, centrifugation, chromatography, extraction, distillation, concentration, precipitation, crystallization and drying.
The advantages of the present invention over the other reported methods are: (i) cost effective process
(ii) higher productivity of compound of Formula I with feeding
(iii) self-contained bioreactor decreases hazardous exposure and risk of contamination. The following Examples further illustrate the invention, it being understood that the invention is not intended to be limited by the details disclosed therein. EXAMPLE 1
A well grown slant of Streptomyces hygroscopicus was taken and 5ml of distilled water was added. It was shaken thoroughly and 4ml of this spore suspension was used for the inoculation of 400ml seed medium taken in 2000 ml conical flask. The composition of seed medium is as follows: Glucose = 20g L
Defatted toasted soyaflour = 40g/L Ammonium sulphate = 3g/L Calcium carbonate = 1.5g L pH of this medium is adjusted to 7 after making up the volume with water. The seed flasks were grown at 28°C for 4 days and used as an inoculum for solid state fermentation.
Solid state fermentation: lOgm each of wheat bran, maize flakes, wheat rawa, rice rawa, oat meal, maize bran, rice bran, were taken in separate petri plates. Adequate amount of water was added and sterilized at 121 deg C for 30 minutes. 10 ml inoculum from 4 day old seed meclium was added. The entire substrate was mixed properly with the inoculum and incubated at 28 deg C for 7 days. Following results were obtained.
Figure imgf000008_0001
EXAMPLE 2
Solid state fermentation was conducted as in Example 1 using 75 g ceramic beads as the solid support in a petri-plate, 15 mL of. Streptomyces hygroscopicus inoculum grown in seed medium was added. The result obtained is given in the table below.
Figure imgf000009_0001
EXAMPLE 3
Solid state fermentation was conducted as in Example 1 using different solid supports in combination. lOgm of this substrate is taken in petri plate and 10ml of Streptomyces hygroscopicus inoculum grown in seed medium was added. The results obtained are given in the table below.
Figure imgf000009_0002
EXAMPLE 4
Solid state fermentation was conducted as in Example 3 using a mixture of wheat bran, wheat rawa and oat meal. lOgm of this substrate is taken in petri plate and 10ml of Streptomyces hygroscopicus inoculum grown in seed medium was added along with a liquid nutrient feed consisting of glucose and dried yeast. The feed was added every alternate day up to 4th day.
Figure imgf000010_0001
EXAMPLE 5
Seed inoculum of Streptomyces hygroscopicus is obtained as explained in Example 1. 3.5L of this inoculum was used for inoculating 35 L of the same seed medium taken in a 50L fermenter. This is grown for 48 hr at 28°C. This is used as an inoculum for solid state fermentation. 15 kg of substrate mixture consisting of wheat bran, wheat rawa and oat meal was loaded into a bioreactor having 22600 cm2 surface area. The bioreactor was sterilised at 121 deg C for 1 to 2 hours using steam. After the sterilization the temperature of the solid substrate was brought down to 28 deg C. 15 L of the above inoculum was added to the solid substrate along with 2 L of glucose and dried yeast feed and mixed. This was incubated at 27 to 29 deg C. On 2nd and 4th day 2 L of the above feed was added to the solid substrate matrix and mixed well. The entire biomass along with the solid substrate was harvested on 7 day and processed to get pharmaceutically acceptable grade of rapamycin.

Claims

We claim:
1. A process of manufacture of a compound of formula I or it's salts from a microorganism capable of producing compound comprising
Formula I
Figure imgf000011_0001
- preparing an inoculum of the said micro-organism, inoculating the solid state substrate with the said inoculum, incubating the said inoculated solid substrate matrix and extracting the said incubated solid substrate matrix to obtain the said compound.
2. A process as claimed in claim 1, wherein the solid substrate fermentation is carried out using Streptomyces hygroscopius.
3. A process as claimed in claim 1, wherein the solid substrate for fermentation is selected from wheat bran, wheat rawa, oat meal, broken wheat, boiled rice, rice bran, rice rawa, beaten rice, maize bran, maize grits, oat bran, bagasse, tapioca residue, soy grits, soy flakes, rice flakes, ceramic beads, glass beads, sponge or a mixture of two or more of these.
4. A process as claimed in claim 1, wherein the solid substrate fermentation is a fed-batch fermentation.
5. A process as claimed in claim 4, wherein the feeding for fed-batch fermentation is done at the beginning of the fermentation or at intervals throughout the fermentation.
6. A process as claimed in claim 4 - 5, wherein the carbon source for feeding is selected from glucose, sucrose, starch (maize, wheat, tapioca, potato), modified starch, maltose, malto-dextrin, soybean oil, acetate or a mixture of two or more of these.
7. A process as claimed in claim 4 - 5, wherein the nitrogen source for feeding is selected from ammonium sulphate, dried yeast, ammonium nitrate, sodium nitrate, bacteriological peptone, yeast extract, casein hydrolyzate, soy peptone, soy flour, cotton seed flour, corn steep liquor or a mixture of two or more of these.
8. A process as claimed in claim 1 wherein the inoculated solid substrate matrix is incubated for 4- 7 days at 25 - 30 °C.
π
PCT/IN2002/000185 2002-09-09 2002-09-09 Solid state fermentation and fed batch for the production of an immunosuppressant WO2004022767A1 (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013153554A1 (en) 2012-04-12 2013-10-17 Natco Pharma Limited Fermentation process for the production of rapamycin

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1436447A (en) * 1972-09-29 1976-05-19 Ayerst Mckenna & Harrison Rapamycin and process of preparation

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1436447A (en) * 1972-09-29 1976-05-19 Ayerst Mckenna & Harrison Rapamycin and process of preparation

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
FANG A.: "Growth of streptomyces hygroscopicus in rotating-wall bioreactor under simulated microgravity inhibits rapamycin production", APPL. MICROBIOL. BIOTECHNOL., vol. 54, 2000, pages 33 - 36 *
KOJIMA I. ET AL.: "Carbon source nutrition of rapamycin biosynthesis in streptomyces hygroscopicus", JOURNAL OF INDUSTRIAL MICROBIOLOGY, vol. 14, 1995, pages 436 - 439 *
LEE M.S. ET AL.: "Effect of nitrogen source on biosynthesis of rapamycin by streptomyes hygroscopicus", JOURNAL OF INDUSTRIAL MICROBIOLOGY & BIOTECHNOLOGY, vol. 19, 1997, pages 83 - 86 *
SCHUHMANN E. AND BERGTER F.: "Mikroskopische untersuchungen zur wachstumskinetik von streptomyces hygroscopicus", ZEITSCHRIFT FUR ALLG. MIKROBIOLOGIE, vol. 16, no. 3, 1976, pages 201 - 215 *
SEHGAL S.N. ET AL.: "Rapamycin (AY-22,989), a new antifungal antibiotic", THE JOURNAL OF ANTIBIOTICS, vol. 28, no. 10, 1975, pages 727 - 732 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013153554A1 (en) 2012-04-12 2013-10-17 Natco Pharma Limited Fermentation process for the production of rapamycin
US9365880B2 (en) 2012-04-12 2016-06-14 Natco Pharma Limited Fermentation process for the production of rapamycin

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