ITMI20121406A1 - PROCEDURE FOR THE PRODUCTION OF TIACUMICINA B - Google Patents
PROCEDURE FOR THE PRODUCTION OF TIACUMICINA B Download PDFInfo
- Publication number
- ITMI20121406A1 ITMI20121406A1 IT001406A ITMI20121406A ITMI20121406A1 IT MI20121406 A1 ITMI20121406 A1 IT MI20121406A1 IT 001406 A IT001406 A IT 001406A IT MI20121406 A ITMI20121406 A IT MI20121406A IT MI20121406 A1 ITMI20121406 A1 IT MI20121406A1
- Authority
- IT
- Italy
- Prior art keywords
- process according
- emulsifier
- production
- tiacumicin
- fermentation
- Prior art date
Links
- 238000004519 manufacturing process Methods 0.000 title claims description 22
- 238000000034 method Methods 0.000 title claims description 21
- ZVGNESXIJDCBKN-UUEYKCAUSA-N fidaxomicin Chemical compound O([C@@H]1[C@@H](C)O[C@H]([C@H]([C@H]1O)OC)OCC\1=C/C=C/C[C@H](O)/C(C)=C/[C@@H]([C@H](/C(C)=C/C(/C)=C/C[C@H](OC/1=O)[C@@H](C)O)O[C@H]1[C@H]([C@@H](O)[C@H](OC(=O)C(C)C)C(C)(C)O1)O)CC)C(=O)C1=C(O)C(Cl)=C(O)C(Cl)=C1CC ZVGNESXIJDCBKN-UUEYKCAUSA-N 0.000 claims description 26
- 229960000628 fidaxomicin Drugs 0.000 claims description 26
- 238000000855 fermentation Methods 0.000 claims description 24
- 230000004151 fermentation Effects 0.000 claims description 24
- 239000003995 emulsifying agent Substances 0.000 claims description 19
- 235000015112 vegetable and seed oil Nutrition 0.000 claims description 12
- 239000008158 vegetable oil Substances 0.000 claims description 12
- 241001404671 Dactylosporangium aurantiacum subsp. hamdenensis Species 0.000 claims description 11
- 239000002518 antifoaming agent Substances 0.000 claims description 9
- 239000013530 defoamer Substances 0.000 claims description 9
- 235000012424 soybean oil Nutrition 0.000 claims description 8
- 239000003549 soybean oil Substances 0.000 claims description 8
- 244000005700 microbiome Species 0.000 claims description 5
- 241001495431 Dactylosporangium aurantiacum Species 0.000 claims description 4
- 239000001963 growth medium Substances 0.000 claims description 4
- 239000004359 castor oil Substances 0.000 claims description 3
- 235000019438 castor oil Nutrition 0.000 claims description 3
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 claims description 3
- 244000068988 Glycine max Species 0.000 claims description 2
- 235000010469 Glycine max Nutrition 0.000 claims description 2
- 244000020551 Helianthus annuus Species 0.000 claims description 2
- 235000003222 Helianthus annuus Nutrition 0.000 claims description 2
- 240000007817 Olea europaea Species 0.000 claims description 2
- 235000019483 Peanut oil Nutrition 0.000 claims description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 2
- 239000000312 peanut oil Substances 0.000 claims description 2
- 239000002609 medium Substances 0.000 description 19
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 12
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 7
- 229920002472 Starch Polymers 0.000 description 7
- 229940041514 candida albicans extract Drugs 0.000 description 7
- 239000008121 dextrose Substances 0.000 description 7
- 238000011534 incubation Methods 0.000 description 7
- 239000004615 ingredient Substances 0.000 description 7
- 239000002054 inoculum Substances 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- 235000019698 starch Nutrition 0.000 description 7
- 239000008107 starch Substances 0.000 description 7
- 230000001954 sterilising effect Effects 0.000 description 7
- 238000004659 sterilization and disinfection Methods 0.000 description 7
- 239000012138 yeast extract Substances 0.000 description 7
- 235000019764 Soybean Meal Nutrition 0.000 description 6
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 6
- 229910000396 dipotassium phosphate Inorganic materials 0.000 description 6
- 235000019797 dipotassium phosphate Nutrition 0.000 description 6
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 6
- 235000019341 magnesium sulphate Nutrition 0.000 description 6
- 239000004455 soybean meal Substances 0.000 description 6
- 230000015556 catabolic process Effects 0.000 description 4
- 238000006731 degradation reaction Methods 0.000 description 4
- 241000894006 Bacteria Species 0.000 description 3
- 229930187202 Tiacumicin Natural products 0.000 description 3
- 230000003115 biocidal effect Effects 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 239000007857 degradation product Substances 0.000 description 3
- 230000002209 hydrophobic effect Effects 0.000 description 3
- 239000002689 soil Substances 0.000 description 3
- 241000183229 Actinoplanes deccanensis Species 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 241000193163 Clostridioides difficile Species 0.000 description 2
- 238000009825 accumulation Methods 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 229940088710 antibiotic agent Drugs 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 230000001804 emulsifying effect Effects 0.000 description 2
- 235000015097 nutrients Nutrition 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 241000186361 Actinobacteria <class> Species 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 241001112696 Clostridia Species 0.000 description 1
- 206010022678 Intestinal infections Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241000187479 Mycobacterium tuberculosis Species 0.000 description 1
- 241000364057 Peoria Species 0.000 description 1
- ZVGNESXIJDCBKN-WUIGKKEISA-N R-Tiacumicin B Natural products O([C@@H]1[C@@H](C)O[C@H]([C@H]([C@H]1O)OC)OCC1=CC=CC[C@H](O)C(C)=C[C@@H]([C@H](C(C)=CC(C)=CC[C@H](OC1=O)[C@@H](C)O)O[C@H]1[C@H]([C@@H](O)[C@H](OC(=O)C(C)C)C(C)(C)O1)O)CC)C(=O)C1=C(O)C(Cl)=C(O)C(Cl)=C1CC ZVGNESXIJDCBKN-WUIGKKEISA-N 0.000 description 1
- 229940122277 RNA polymerase inhibitor Drugs 0.000 description 1
- 239000003463 adsorbent Substances 0.000 description 1
- 238000005273 aeration Methods 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 239000002537 cosmetic Substances 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- AIUDWMLXCFRVDR-UHFFFAOYSA-N dimethyl 2-(3-ethyl-3-methylpentyl)propanedioate Chemical compound CCC(C)(CC)CCC(C(=O)OC)C(=O)OC AIUDWMLXCFRVDR-UHFFFAOYSA-N 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 238000005187 foaming Methods 0.000 description 1
- 244000005709 gut microbiome Species 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 150000007931 macrolactones Chemical class 0.000 description 1
- 239000000693 micelle Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000036457 multidrug resistance Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000013587 production medium Substances 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 231100000765 toxin Toxicity 0.000 description 1
- 108700012359 toxins Proteins 0.000 description 1
- 238000009423 ventilation Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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
- C12P19/00—Preparation of compounds containing saccharide radicals
- C12P19/44—Preparation of O-glycosides, e.g. glucosides
- C12P19/60—Preparation of O-glycosides, e.g. glucosides having an oxygen of the saccharide radical directly bound to a non-saccharide heterocyclic ring or a condensed ring system containing a non-saccharide heterocyclic ring, e.g. coumermycin, novobiocin
- C12P19/62—Preparation of O-glycosides, e.g. glucosides having an oxygen of the saccharide radical directly bound to a non-saccharide heterocyclic ring or a condensed ring system containing a non-saccharide heterocyclic ring, e.g. coumermycin, novobiocin the hetero ring having eight or more ring members and only oxygen as ring hetero atoms, e.g. erythromycin, spiramycin, nystatin
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Zoology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Wood Science & Technology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Microbiology (AREA)
- General Chemical & Material Sciences (AREA)
- Biotechnology (AREA)
- Health & Medical Sciences (AREA)
- Biochemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Crystals, And After-Treatments Of Crystals (AREA)
- Game Rules And Presentations Of Slot Machines (AREA)
Description
“PROCEDIMENTO PER LA PRODUZIONE DI TIACUMICINA B†⠀ œPROCESS FOR THE PRODUCTION OF TIACUMICIN Bâ €
CAMPO DELL’INVENZIONE FIELD OF INVENTION
La presente invenzione si riferisce a un procedimento migliorato di produzione di Tiacumicina B ed in particolar modo ad un metodo di fermentazione che consente di incrementare la produzione di Tiacumicina B e di prevenirne la sua degradazione nel brodo di coltura. The present invention refers to an improved production process of Tiacumicin B and in particular to a fermentation method which allows to increase the production of Tiacumicin B and to prevent its degradation in the culture broth.
TECNICA PRECEDENTE PREVIOUS TECHNIQUE
La Tiacumicina B, nota anche come Fidaxomicina, appartiene ad una famiglia di macrolattoni, prodotti da actinomiceti, con una storia complessa. Tiacumicin B, also known as Fidaxomicin, belongs to a family of macrolactones, produced by actinomycetes, with a complex history.
La Tiacumicina B, infatti, ha la stessa struttura della lipiarmycina che fu isolata e descritta da Lepetit nel 1976 in US3,978,211 come nuovo antibiotico prodotto mediante coltivazione di Actinoplanes deccanensis A/10655 ATCC21983. Tiacumicin B, in fact, has the same structure as lipiarmycin which was isolated and described by Lepetit in 1976 in US3,978,211 as a new antibiotic produced by cultivation of Actinoplanes deccanensis A / 10655 ATCC21983.
Il primo brevetto rivendicava il prodotto lipiarmycina ed un metodo di fermentazione per produrla utilizzando Actinoplanes deccanensis in un terreno nutritivo contenente fonti assimilabili di carbonio, azoto e sali inorganici. The first patent claimed the lipiarmycin product and a fermentation method to produce it using Actinoplanes deccanensis in a nutrient medium containing assimilable sources of carbon, nitrogen and inorganic salts.
Nel 1986, Abbott Laboratories, depositava un nuovo brevetto US 4,918,174 relativo allo stesso prodotto, che in questo caso era chiamato Tiacumicina B, ottenuto da Dactylosporangium aurantiacum subsp. hamdenensis. In 1986, Abbott Laboratories, filed a new US patent 4,918,174 relating to the same product, which in this case was called Tiacumicin B, obtained from Dactylosporangium aurantiacum subsp. hamdenensis.
Il ceppo produttore fu depositato all’ARS Patent Collection del Northern Regional Research Center di Peoria, dove gli fu assegnato il numero di accesso NRRL 18085. The producing strain was deposited in the ARS Patent Collection of the Northern Regional Research Center in Peoria, where it was assigned the NRRL access number 18085.
Il brevetto rivendicava le Tiacumicine ed un procedimento per produrre Tiacumicine tramite coltivazione di Dactylosporangium aurantiacum subsp. hamdenensis in un terreno nutritivo. The patent claimed Tiacumicins and a process for producing Tiacumicins by cultivating Dactylosporangium aurantiacum subsp. hamdenensis in a nutrient medium.
Più recentemente, Optimer Pharmaceutical ha depositato un nuovo brevetto US 7,507,564 che descrive un procedimento migliorato per la produzione di Tiacumicine allo scopo di ottenere una resa superiore a 50 mcg/ml. More recently, Optimer Pharmaceutical has filed a new US patent 7,507,564 which describes an improved process for the production of Tiacumicine in order to obtain a yield greater than 50 mcg / ml.
Il procedimento descritto da Optimer à ̈ ancora basato sulla fermentazione di Dactylosporangium aurantiacum, ma in un terreno di fermentazione contenente una resina adsorbente in grado di adsorbire la Tiacumicina B. The procedure described by Optimer is still based on the fermentation of Dactylosporangium aurantiacum, but in a fermentation medium containing an adsorbent resin capable of adsorbing Tiacumicin B.
La Tiacumicina B Ã ̈ un inibitore della RNA polimerasi. Tiacumicin B is an RNA polymerase inhibitor.
Il grande interesse nei confronti della Tiacumicina B à ̈ dovuto alla sua attività biologica contro il batterio multiresistente (hospital superbug) Clostridium difficile. The great interest in Tiacumicin B is due to its biological activity against the multidrug-resistant bacterium (hospital superbug) Clostridium difficile.
Il C. difficile à ̈ un batterio sporigeno anaerobio Gram-positivo che può provocare gravi infezioni intestinali attraverso la produzione di tossine. C. difficile is a Gram-positive anaerobic spore-forming bacterium that can cause severe intestinal infections through the production of toxins.
La Tiacumicina B à ̈ un antibiotico a spettro ristretto con una buona attività nei confronti dei clostridi e un’attività minima verso la restante microflora intestinale. Tiacumicin B is a narrow spectrum antibiotic with good activity against clostridia and minimal activity towards the remaining intestinal microflora.
La specificità può essere importante per la riduzione del tasso di ricaduta (recidiva) che si osserva con gli antibiotici ad ampio spettro, poiché il mantenimento dell’equilibrio naturale dei batteri intestinali aiuta a fornire resistenza alla ricolonizzazione da parte dei patogeni. Specificity may be important for reducing the relapse rate (relapse) seen with broad-spectrum antibiotics, as maintaining the natural balance of intestinal bacteria helps provide resistance to pathogen recolonization.
Recentemente à ̈ stato dimostrato che la Tiacumicina B à ̈ efficace contro il Mycobacterium tuberculosis dotato di resistenza multidrug e presenta anche buona attività antitumorale. Tiacumicin B has recently been shown to be effective against Mycobacterium tuberculosis with multidrug resistance and also has good anticancer activity.
DESCRIZIONE DELL’INVENZIONE DESCRIPTION OF THE INVENTION
La presente invenzione si riferisce ad un procedimento migliorato per la produzione della Tiacumicina B e, particolarmente, all’uso nella fermentazione, di prodotti emulsionanti e/o antischiuma ed opzionalmente oli vegetali. The present invention refers to an improved process for the production of Thiacumicin B and, particularly, to the use in fermentation of emulsifying and / or antifoam products and optionally vegetable oils.
L’introduzione nel terreno di coltura o nel corso della fermentazione di questi composti, favorisce la produzione di Tiacumicina B e protegge la molecola dal degrado che si verifica naturalmente durante la fermentazione. The introduction of these compounds into the culture medium or during fermentation favors the production of Tiacumicin B and protects the molecule from the degradation that occurs naturally during fermentation.
Il microorganismo preferibilmente utilizzato à ̈ Dactylosporangium aurantiacum subsp. hamdenensis. The microorganism preferably used is Dactylosporangium aurantiacum subsp. hamdenensis.
Si osserva frequentemente, nella biosintesi degli antibiotici, un effetto di regolazione feed-back che limita le potenzialità produttive. Allo stesso modo, la bassa resistenza del microrganismo produttore all’antibiotico sintetizzato, può limitare la produttività fermentativa. A feed-back regulating effect is frequently observed in the biosynthesis of antibiotics, which limits production potential. Likewise, the low resistance of the producer microorganism to the synthesized antibiotic can limit the fermentation productivity.
Analizzando nello specifico la fermentazione della Tiacumicina B si nota che, con l’aumentare dell’età di fermentazione, una volta raggiunto il picco massimo di produttività , compaiono dei prodotti di degrado e la concentrazione di Tiacumicina B diminuisce in modo proporzionale. Analyzing specifically the fermentation of Tiacumicin B it can be seen that, with the increase in the age of fermentation, once the maximum productivity peak is reached, degradation products appear and the concentration of Tiacumicin B decreases proportionally.
L’ambiente di fermentazione non à ̈ favorevole ai composti chimicamente instabili. La variazione del pH, l’accumulo di cataboliti e la presenza di attività enzimatiche nel mezzo acquoso, sono tutte condizioni che concorrono alla degradazione dei composti instabili. The fermentation environment is not conducive to chemically unstable compounds. The pH variation, the accumulation of catabolites and the presence of enzymatic activities in the aqueous medium are all conditions that contribute to the degradation of unstable compounds.
È stato osservato, sorprendentemente, che l’aggiunta di una miscela costituita da un emulsionante e/o un antischiuma ed opzionalmente un olio vegetale permette di evitare l’instaurarsi di fenomeni di inibizione ed, allo stesso tempo, di preservare il prodotto dalla degradazione. It has been surprisingly observed that the addition of a mixture consisting of an emulsifier and / or an antifoam and optionally a vegetable oil allows to avoid the establishment of inhibition phenomena and, at the same time, to preserve the product from degradation.
La Tiacumicina B Ã ̈ un prodotto liposolubile che viene rilasciato, durante la fermentazione, nel terreno di coltura. Tiacumicin B is a fat-soluble product that is released, during fermentation, into the culture medium.
È stato sorprendentemente osservato, analizzando il brodo di fermentazione con analisi HPLC, che la produzione di Tiacumicina B nel terreno così modificato, continua ad incrementare nel corso della fermentazione fino a 168h senza che compaiano prodotti di degrado in quantità significativa. It has been surprisingly observed, by analyzing the fermentation broth with HPLC analysis, that the production of Tiacumicin B in the soil thus modified, continues to increase during the fermentation up to 168h without any significant degradation products appearing.
Oggetto della presente invenzione à ̈ un procedimento per la produzione di Tiacumicina B comprendente la fermentazione di un microorganismo della specie Dactylosporangium aurantiacum, preferibilmente Dactylosporangium aurantiacum subsp. Hamdenensis, in un brodo di cultura contenente un emulsionante e/o un antischiuma ed opzionalmente un olio vegetale. The object of the present invention is a process for the production of Tiacumicin B comprising the fermentation of a microorganism of the species Dactylosporangium aurantiacum, preferably Dactylosporangium aurantiacum subsp. Hamdenensis, in a culture broth containing an emulsifier and / or an antifoam and optionally a vegetable oil.
Gli emulsionanti sono costituiti da una componente idrofobica ed una idrofilica. Alcuni derivati dell’olio di ricino, etossilati, vengono utilizzati in formulazioni farmaceutiche per applicazioni orali, topiche o parenterali ed in campo cosmetico e per l’alimentazione animale. Emulsifiers consist of a hydrophobic and a hydrophilic component. Some castor oil derivatives, ethoxylated, are used in pharmaceutical formulations for oral, topical or parenteral applications and in the cosmetic field and for animal feed.
Gli emulsionanti consentono di ottenere delle emulsioni stabili “olio in acqua†ed “acqua in olio†. The emulsifiers allow to obtain stable emulsions â € œoil in waterâ € and â € œwater in oilâ €.
L’utilizzo di un emulsionante consente di favorire il passaggio di sostanze idrofobiche in acqua formando delle micelle che presentano all’ambiente acquoso la parte idrofilica e legano, al loro interno, la sostanza non idrosolubile. The use of an emulsifier allows to favor the passage of hydrophobic substances in water by forming micelles which have the hydrophilic part in the aqueous environment and bind the insoluble substance inside them.
È stato osservato, sorprendentemente, che la presenza nel terreno di fermentazione di un emulsionante favorisce la produzione di Tiacumicina B permettendo di ottenere produttività 10 volte superiori rispetto a quelle ottenibili con il terreno base. It has been surprisingly observed that the presence in the fermentation medium of an emulsifier favors the production of Tiacumicin B allowing to obtain productivity 10 times higher than those obtainable with the base medium.
In particolar modo risulta positivo l’utilizzo di un emulsionante, derivato etossilato dell’olio di ricino, con un bilancio idrofilico/lipofilico di circa 14 (HLB 14) utilizzato in concentrazioni comprese tra 0,5 e 30 g/L. In particular, the use of an emulsifier, an ethoxylated derivative of castor oil, with a hydrophilic / lipophilic balance of about 14 (HLB 14) used in concentrations between 0.5 and 30 g / L, is positive.
Analogamente à ̈ stato osservato che la produzione della Tiacumicina B à ̈ favorita, sebbene in maniera più modesta, dall’addizione al terreno di fermentazione di un antischiuma. Gli antischiuma sono anch’essi costituiti da una componente idrofilica ed una idrofobica. Similarly, it has been observed that the production of Tiacumicin B is favored, albeit in a more modest way, by the addition of an antifoam to the fermentation medium. Defoamers are also made up of a hydrophilic and a hydrophobic component.
L’utilizzo di un antischiuma del tipo poli-alchil-glicole ed in particolar modo di un alchil-poli-alcossi-etere, permette di raddoppiare la produttività rispetto al terreno base. Preferibilmente l’antischiuma à ̈ addizionato al terreno in concentrazione 0,5÷30 g/L. The use of an antifoam of the poly-alkyl-glycol type and in particular of an alkyl-poly-alkoxy-ether, allows to double the productivity compared to the basic soil. Preferably, the antifoam is added to the soil in a concentration of 0.5à · 30 g / L.
L’utilizzo di prodotti emulsionanti in fermentatore à ̈ limitato dalla difficoltà , in condizioni d’areazione ed agitazione del brodo, di controllare l’elevata formazione di schiuma che essi determinano. The use of emulsifying products in the fermenter is limited by the difficulty, in conditions of aeration and stirring of the broth, to control the high foam formation they cause.
È stato sorprendentemente osservato che, se l’emulsionante viene utilizzato in combinazione con prodotti antischiuma o in combinazione con antischiuma ed oli vegetali, non si incorre in problemi di elevata formazione di schiuma e la produzione della Tiacumicina B risulta ulteriormente favorita. It has been surprisingly observed that, if the emulsifier is used in combination with defoamers or in combination with defoamers and vegetable oils, there is no problem of high foaming and the production of Tiacumicin B is further favored.
In particolare l’olio vegetale à ̈ scelto nel gruppo costituito da olio di soia, girasole, oliva, arachidi, particolarmente preferito à ̈ l’olio di soia. Preferibilmente l’olio vegetale ha una concentrazione nel brodo di coltura compresa tra 0,5 g/L e 50 g/L. In particular, vegetable oil is chosen from the group consisting of soybean, sunflower, olive, peanut oil, particularly preferred is soybean oil. Preferably, vegetable oil has a concentration in the culture broth between 0.5 g / L and 50 g / L.
L’assenza, o per lo meno l’accumulo minimo, di prodotti di degradazione permette di ottenere una maggiore concentrazione di Tiacumicina B nel brodo. The absence, or at least the minimal accumulation, of degradation products allows to obtain a higher concentration of Tiacumicin B in the broth.
Inoltre, dato che il brodo contiene come prodotto prevalentemente la Furthermore, since the broth mainly contains the
Tiacumicina B, il recupero e la purificazione dello stesso dal brodo di Tiacumicin B, the recovery and purification of the same from the broth of
fermentazione diventa più efficiente. fermentation becomes more efficient.
Appare evidente che la presenza di un prodotto prevalentemente puro It is evident that the presence of a predominantly pure product
nel brodo semplifichi il processo di recupero e permetta di evitare stadi di in the broth simplify the recovery process and allow to avoid stages of
purificazione lunghi e dispendiosi. time-consuming and expensive purification.
L’emulsionante e/o l’antischiuma e opzionalmente l’olio vegetale The emulsifier and / or the defoamer and optionally the vegetable oil
possono essere presenti nel terreno di coltura. alternativamente l’emulsionante may be present in the culture medium. alternatively the emulsifier
e l’antischiuma possono essere aggiunti all’inizio della produzione della and antifoam can be added at the start of production of the
Tiacumicina B in un'unica volta o gradualmente durante la fermentazione. Tiacumicin B at one time or gradually during fermentation.
ESEMPIO 1 (comparativo) EXAMPLE 1 (comparative)
Dactylosporangium aurantiacum subsp. hamdenensis AB718C-41 Dactylosporangium aurantiacum subsp. hamdenensis AB718C-41
NRRL18085 fu mantenuto a -180°C (WCB). La coltura stock fu usata per NRRL18085 was maintained at -180 ° C (WCB). The stock culture was used for
inoculare una beuta (seed flask) contenente 40 ml di terreno vegetativo VPF-1 inoculate a seed flask containing 40 ml of VPF-1 vegetative medium
(Tabella 1) che fu incubata su un agitatore rotante per 48h a 30°C e 250÷300 rpm. (Table 1) which was incubated on a rotating shaker for 48h at 30 ° C and 250à · 300 rpm.
INGREDIENTE 1 L INGREDIENT 1 L
Estratto lievito 7,5 g Yeast extract 7.5 g
Destrosio 1 g Dextrose 1 g
Amido solubile 24 g Soluble starch 24 g
Peptone di soia 7,5 g Soy peptone 7.5 g
CaCO34 g CaCO34 g
pH corretto a 7.3 pH corrected to 7.3
Sterilizzazione 121C° x 30 min Sterilization 121C ° x 30 min
Tabella 1. terreno vegetativo VPF-1 Table 1. VPF-1 vegetative medium
Al termine dell’incubazione, la coltura vegetativa fu trasferita At the end of the incubation, the vegetative culture was transferred
asetticamente (0,8% di inoculo) in una beuta contenente 30 ml di terreno produttivo PF-1 (tabella 2) che fu incubata su agitatore rotante a 30°C e aseptically (0.8% inoculum) in a flask containing 30 ml of PF-1 production medium (table 2) which was incubated on a rotary shaker at 30 ° C and
250÷300 rpm per 96h raggiungendo una produttività di 50mcg/ml. 250à · 300 rpm for 96h reaching a productivity of 50mcg / ml.
INGREDIENTE 1 L INGREDIENT 1 L
Destrosio 20 g Dextrose 20 g
Amido 20g Starch 20g
Farina di soia 10 g Soybean meal 10 g
Estratto lievito 3 g Yeast extract 3 g
Olio di soia 1 g Soybean oil 1 g
K2HPO4*7H2O 0,05 g K2HPO4 * 7H2O 0.05 g
MgSO4*7H2O 0,05 g MgSO4 * 7H2O 0.05 g
KCl 0,03 KCl 0.03
CaCO33 g CaCO33 g
Senza correzione del pH Without pH correction
Sterilizzazione 121C° x 30 min Sterilization 121C ° x 30 min
Tabella 2. terreno produttivo PF-1 Table 2. PF-1 productive land
ESEMPIO 2 EXAMPLE 2
Dactylosporangium aurantiacum subsp. hamdenensis AB718C-41 Dactylosporangium aurantiacum subsp. hamdenensis AB718C-41
NRRL18085 fu mantenuto a -180°C (WCB). La coltura stock fu usata per NRRL18085 was maintained at -180 ° C (WCB). The stock culture was used for
inoculare una beuta (seed flask) contenente 40 ml di terreno vegetativo VPF-1 inoculate a seed flask containing 40 ml of VPF-1 vegetative medium
(Tabella 1) che fu incubata su un agitatore rotante per 48h a 30°C e 250÷300 (Table 1) which was incubated on a rotating shaker for 48h at 30 ° C and 250à · 300
rpm. Al termine dell’incubazione, la coltura vegetativa fu trasferita rpm. At the end of the incubation, the vegetative culture was transferred
asetticamente (0,8% di inoculo) in una beuta contenente 30 ml di terreno aseptically (0.8% inoculum) in a flask containing 30 ml of medium
produttivo PF-2 (tabella 3) che fu incubata su agitatore rotante a 30°C e production PF-2 (table 3) which was incubated on a rotary shaker at 30 ° C e
250÷300 rpm per 96h raggiungendo una produttività di 125 mcg/ml. 250à · 300 rpm for 96h reaching a productivity of 125 mcg / ml.
INGREDIENTE 1 L INGREDIENT 1 L
Destrosio 20 g Dextrose 20 g
Amido 20g Starch 20g
Farina di soia 10 g Soybean meal 10 g
Estratto lievito 3 g Yeast extract 3 g
Olio di soia 1 g Soybean oil 1 g
K2HPO4*7H2O 0,05 g K2HPO4 * 7H2O 0.05 g
MgSO4*7H2O 0,05 g MgSO4 * 7H2O 0.05 g
KCl 0,03 KCl 0.03
CaCO33 g CaCO33 g
antischiuma 5g 5g defoamer
Senza correzione del pH Without pH correction
Sterilizzazione 121C° x 30 min Sterilization 121C ° x 30 min
Tabella 3: terreno produttivo PF-2 Table 3: PF-2 productive land
ESEMPIO 3 EXAMPLE 3
Dactylosporangium aurantiacum subsp. hamdenensis AB718C-41 Dactylosporangium aurantiacum subsp. hamdenensis AB718C-41
NRRL18085 fu mantenuto a -180°C (WCB). La coltura stock fu usata per NRRL18085 was maintained at -180 ° C (WCB). The stock culture was used for
inoculare una beuta (seed flask) contenente 40 ml di terreno vegetativo VPF-1 inoculate a seed flask containing 40 ml of VPF-1 vegetative medium
(Tabella 1) che fu incubata su un agitatore rotante per 48h a 30°C e 250÷300 (Table 1) which was incubated on a rotating shaker for 48h at 30 ° C and 250à · 300
rpm. Al termine dell’incubazione, la coltura vegetativa fu trasferita rpm. At the end of the incubation, the vegetative culture was transferred
asetticamente (0,8% di inoculo) in una beuta contenente 30 ml di terreno aseptically (0.8% inoculum) in a flask containing 30 ml of medium
produttivo PF-3 (tabella 4) che fu incubata su agitatore rotante a 30°C e production PF-3 (table 4) which was incubated on a rotary shaker at 30 ° C e
250÷300 rpm per 168h raggiungendo una produttività di 470 mcg/ml. 250à · 300 rpm for 168h reaching a productivity of 470 mcg / ml.
INGREDIENTE 1 L INGREDIENT 1 L
Destrosio 20 g Dextrose 20 g
Amido 40g Starch 40g
Farina di soia 10 g Soybean meal 10 g
Estratto lievito 3 g Yeast extract 3 g
Olio di soia 1 g Soybean oil 1 g
K2HPO4*7H2O 0,05 g K2HPO4 * 7H2O 0.05 g
MgSO4*7H2O 0,05 g MgSO4 * 7H2O 0.05 g
KCl 0,03 KCl 0.03
CaCO33 g CaCO33 g
emulsionante 15g emulsifier 15g
Senza correzione del pH Without pH correction
Sterilizzazione 121C° x 30 min Sterilization 121C ° x 30 min
Tabella 4: terreno produttivo PF-3 Table 4: PF-3 productive land
ESEMPIO 4 EXAMPLE 4
Dactylosporangium aurantiacum subsp. hamdenensis AB718C-41 Dactylosporangium aurantiacum subsp. hamdenensis AB718C-41
NRRL18085 fu mantenuto a -180°C (WCB). La coltura stock fu usata per NRRL18085 was maintained at -180 ° C (WCB). Stock culture was used for
inoculare una beuta (seed flask) contenente 40 ml di terreno vegetativo VPF-1 inoculate a seed flask containing 40 ml of VPF-1 vegetative medium
(Tabella 1) che fu incubata su un agitatore rotante per 48h a 30°C e 250÷300 (Table 1) which was incubated on a rotating shaker for 48h at 30 ° C and 250à · 300
rpm. Al termine dell’incubazione, la coltura vegetativa fu trasferita rpm. At the end of the incubation, the vegetative culture was transferred
asetticamente (0,8% di inoculo) in una beuta contenente 30 ml di terreno aseptically (0.8% inoculum) in a flask containing 30 ml of medium
produttivo PF-4 (tabella 5) che fu incubata su agitatore rotante a 30°C e production PF-4 (table 5) which was incubated on a rotary shaker at 30 ° C e
250÷300 rpm per 168h raggiungendo una produttività di 750mcg/ml. 250à · 300 rpm for 168h reaching a productivity of 750mcg / ml.
INGREDIENTE 1 L INGREDIENT 1 L
Destrosio 20 g Dextrose 20 g
Amido 40g Starch 40g
Farina di soia 10 g Soybean meal 10 g
Estratto lievito 3 g Yeast extract 3 g
Olio di soia 1 g Soybean oil 1 g
K2HPO4*7H2O 0,05 g K2HPO4 * 7H2O 0.05 g
MgSO4*7H2O 0,05 g MgSO4 * 7H2O 0.05 g
KCl 0,03 KCl 0.03
CaCO33 g CaCO33 g
antischiuma 5,5g 5.5g defoamer
emulsionante 5,5g emulsifier 5.5g
Senza correzione del pH Without pH correction
Sterilizzazione 121C° x 30 min Sterilization 121C ° x 30 min
Tabella 5: terreno produttivo PF-4 Table 5: PF-4 productive land
ESEMPIO 5 EXAMPLE 5
Dactylosporangium aurantiacum subsp. hamdenensis AB718C-41 Dactylosporangium aurantiacum subsp. hamdenensis AB718C-41
NRRL18085 fu mantenuto a -180°C (WCB). La coltura stock fu usata per NRRL18085 was maintained at -180 ° C (WCB). Stock culture was used for
inoculare una beuta (seed flask) contenente 40 ml di terreno vegetativo VPF-1 inoculate a seed flask containing 40 ml of VPF-1 vegetative medium
(Tabella 1) che fu incubata su un agitatore rotante per 48h a 30°C e 250÷300 (Table 1) which was incubated on a rotating shaker for 48h at 30 ° C and 250à · 300
rpm. Al termine dell’incubazione, la coltura vegetativa fu trasferita rpm. At the end of the incubation, the vegetative culture was transferred
asetticamente (0,8% di inoculo) in una beuta contenente 30 ml di terreno aseptically (0.8% inoculum) in a flask containing 30 ml of medium
produttivo PF-5 (tabella 6) che fu incubata su agitatore rotante a 30°C e production PF-5 (table 6) which was incubated on a rotary shaker at 30 ° C e
250÷300 rpm per 168h raggiungendo una produttività di 730mcg/ml. 250à · 300 rpm for 168h reaching a productivity of 730mcg / ml.
INGREDIENTE 1 L INGREDIENT 1 L
Destrosio 20 g Dextrose 20 g
Amido 40g Starch 40g
Farina di soia 10 g Soybean meal 10 g
Estratto lievito 3 g Yeast extract 3 g
Olio di soia 6,4 g Soybean oil 6.4 g
K2HPO4*7H2O 0,05 g K2HPO4 * 7H2O 0.05 g
MgSO4*7H2O 0,05 g MgSO4 * 7H2O 0.05 g
KCl 0,03 KCl 0.03
CaCO33 g CaCO33 g
antischiuma 5,5g 5.5g defoamer
emulsionante 5,5g emulsifier 5.5g
Senza correzione del pH Without pH correction
Sterilizzazione 121C° x 30 min Sterilization 121C ° x 30 min
Tabella 6: terreno produttivo PF-5 Table 6: PF-5 productive land
ESEMPIO 6 EXAMPLE 6
Dactylosporangium aurantiacum subsp. hamdenensis AB718C-41 Dactylosporangium aurantiacum subsp. hamdenensis AB718C-41
NRRL18085 fu mantenuto a -180°C (WCB). La coltura stock fu usata per NRRL18085 was maintained at -180 ° C (WCB). Stock culture was used for
inoculare una beuta (seed flask) contenente 40 ml di terreno vegetativo VPF-1 inoculate a seed flask containing 40 ml of VPF-1 vegetative medium
(Tabella 1) che fu incubata su un agitatore rotante per 48h a 30°C e 250÷300 (Table 1) which was incubated on a rotating shaker for 48h at 30 ° C and 250à · 300
rpm. Al termine dell’incubazione, la coltura vegetativa fu trasferita rpm. At the end of the incubation, the vegetative culture was transferred
asetticamente (0,8% di inoculo) in una beuta contenente 30 ml di terreno aseptically (0.8% inoculum) in a flask containing 30 ml of medium
produttivo PF-1/1 (tabella 7) che fu incubata su agitatore rotante a 30°C e production PF-1/1 (table 7) which was incubated on a rotary shaker at 30 ° C e
250÷300 rpm per 72h. A 72h fu aggiunta una soluzione di emulsionante ed 250à · 300 rpm for 72h. At 72h an emulsifier solution was added and
antischiuma in modo da ottenere in terreno produttivo una concentrazione di antifoam in order to obtain a concentration of
11 g/L per entrambi. La fermentazione fu ulteriormente incubata fino a 168h 11 g / L for both. The fermentation was further incubated up to 168h
raggiungendo una produttività di 530 mcg/ml. reaching a productivity of 530 mcg / ml.
INGREDIENTE 1 L INGREDIENT 1 L
Destrosio 20 g Dextrose 20 g
Amido 40g Starch 40g
Farina di soia 10 g Soybean meal 10 g
Estratto lievito 3 g Yeast extract 3 g
Olio di soia 1 g Soybean oil 1 g
K2HPO4*7H2O 0,05 g K2HPO4 * 7H2O 0.05 g
MgSO4*7H2O 0,05 g MgSO4 * 7H2O 0.05 g
KCl 0,03 KCl 0.03
CaCO33 g CaCO33 g
Senza correzione del pH Without pH correction
Sterilizzazione 121C° x 30 min Sterilization 121C ° x 30 min
Tabella 7: terreno produttivo PF-1/1 Table 7: PF-1/1 productive land
ESEMPIO 7 EXAMPLE 7
Dactylosporangium aurantiacum subsp. hamdenensis AB718C-41 Dactylosporangium aurantiacum subsp. hamdenensis AB718C-41
NRRL18085 fu mantenuto a -180°C (WCB). La coltura stock fu usata per NRRL18085 was maintained at -180 ° C (WCB). Stock culture was used for
inoculare 6 beute (seed flask) contenenti 40 ml di terreno vegetativo VPF-1 inoculate 6 seed flasks containing 40 ml of VPF-1 vegetative medium
(Tabella 1) che furono incubate su un agitatore rotante per 48h a 30°C e (Table 1) which were incubated on a rotary shaker for 48h at 30 ° C e
250÷300 rpm. Al termine dell’incubazione, la coltura vegetativa fu trasferita 250à · 300 rpm. At the end of the incubation, the vegetative culture was transferred
asetticamente (1,4% di inoculo) in una fermentatore da 20L contenente 16L di aseptically (1.4% inoculum) in a 20L fermenter containing 16L of
terreno produttivo PF-5 (tabella 6). productive land PF-5 (table 6).
La fermentazione, condotta a 30°C, con areazione 0,75 vvm a The fermentation, carried out at 30 ° C, with ventilation 0.75 vvm a
contropressione 0,5 bar ed agitata a 210÷250 rpm, ha portato ad una back pressure 0.5 bar and agitated at 210à · 250 rpm, led to a
produttività di 440 mcg/ml a 120h di fermentazione. productivity of 440 mcg / ml at 120h of fermentation.
Claims (12)
Priority Applications (9)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT001406A ITMI20121406A1 (en) | 2012-08-07 | 2012-08-07 | PROCEDURE FOR THE PRODUCTION OF TIACUMICINA B |
| DK13750659.8T DK2882860T3 (en) | 2012-08-07 | 2013-07-30 | Enzymatic preparation of thiacumicin B (fidaxomicin) |
| IN928DEN2015 IN2015DN00928A (en) | 2012-08-07 | 2013-07-30 | |
| CN201380041582.1A CN104603279A (en) | 2012-08-07 | 2013-07-30 | Procedure for the production of tiacumicin b |
| EP13750659.8A EP2882860B1 (en) | 2012-08-07 | 2013-07-30 | Enzymatic production of tiacumicin b (fidaxomicin) |
| PCT/EP2013/065994 WO2014023616A1 (en) | 2012-08-07 | 2013-07-30 | Procedure for the production of tiacumicin b |
| CA2881302A CA2881302C (en) | 2012-08-07 | 2013-07-30 | Procedure for the production of tiacumicin b |
| US14/419,955 US9970041B2 (en) | 2012-08-07 | 2013-07-30 | Procedure for the production of tiacumicin B |
| HK15110889.6A HK1210225A1 (en) | 2012-08-07 | 2015-11-04 | Procedure for the production of tiacumicin |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT001406A ITMI20121406A1 (en) | 2012-08-07 | 2012-08-07 | PROCEDURE FOR THE PRODUCTION OF TIACUMICINA B |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ITMI20121406A1 true ITMI20121406A1 (en) | 2014-02-08 |
Family
ID=47016770
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IT001406A ITMI20121406A1 (en) | 2012-08-07 | 2012-08-07 | PROCEDURE FOR THE PRODUCTION OF TIACUMICINA B |
Country Status (1)
| Country | Link |
|---|---|
| IT (1) | ITMI20121406A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2015127955A1 (en) | 2014-02-25 | 2015-09-03 | Olon S.P.A. | A new polymorph of tiacumicin b and process for preparation thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004014295A2 (en) * | 2002-07-29 | 2004-02-19 | Optimer Pharmaceuticals, Inc. | Tiacumicin production |
-
2012
- 2012-08-07 IT IT001406A patent/ITMI20121406A1/en unknown
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004014295A2 (en) * | 2002-07-29 | 2004-02-19 | Optimer Pharmaceuticals, Inc. | Tiacumicin production |
Non-Patent Citations (1)
| Title |
|---|
| ERB ET AL: "From natural product to marketed drug: the tiacumicin odyssey", NATURAL PRODUCT REPORTS, vol. 30, 2013, pages 161 - 174, XP002711994 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2015127955A1 (en) | 2014-02-25 | 2015-09-03 | Olon S.P.A. | A new polymorph of tiacumicin b and process for preparation thereof |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103060248B (en) | Method for constructing gene engineering FK506 high-producing strain and streptomyces tsukubaensis high-producing strain | |
| El-Bondkly et al. | Overproduction and biological activity of prodigiosin-like pigments from recombinant fusant of endophytic marine Streptomyces species | |
| US9970041B2 (en) | Procedure for the production of tiacumicin B | |
| AU2003238752A1 (en) | Mutant actinosynnema pretiosum strain with increased maytansinoid production | |
| WO2003064610A2 (en) | Mutant actinosynnema pretiosum strain with increased maytansinoid production | |
| ITMI20121406A1 (en) | PROCEDURE FOR THE PRODUCTION OF TIACUMICINA B | |
| KR20020092899A (en) | Antibiotic caprazamycins and process for producing the same | |
| ITMI20130856A1 (en) | PROCEDURE FOR THE PRODUCTION OF TIACUMICINA B | |
| JP5818915B2 (en) | Method for producing cyclic lipopeptide compound | |
| Phongsopitanun et al. | Marine Streptomyces chumphonensis KK1-2 T produces piericidin A1 as the major secondary metabolite. | |
| ITMI20120559A1 (en) | IMPROVED PROCEDURE FOR THE PRODUCTION OF TIACUMICINA B | |
| Gulyamova et al. | Effect of epigenetic modifiers on fermentation parameters of endophytic fungi from plants growing in Uzbekistan | |
| Anzai et al. | Production of rosamicin derivatives in Micromonospora rosaria by introduction of d-mycinose biosynthetic gene with Φ C31-derived integration vector pSET152 | |
| CN105002106A (en) | Engineering strains for high yield of platensimycin and platencin and fermentation and separation and purification technologies thereof | |
| US12018305B2 (en) | Process for production of nigericin from Streptomyces sp. MCC-0151 | |
| CN102993168B (en) | Streptonigrin analog and preparation method thereof, purposes | |
| WO2010122669A1 (en) | Novel compound amycolamicin, method for production thereof, and use thereof | |
| CN102391969B (en) | Clostridium AUH-JLC140 and its application in O-desmethylangolensin biosynthesis | |
| CN113396214B (en) | Method for producing nigericin from streptomyces sp.mcc 0151 | |
| CN1263762C (en) | Desugar and deaminosugar FR-008 derived polyketone antibiotics | |
| Zamir et al. | Screening of Actinomycetes Isolated from soil and their Antimicrobial Activity against Plant Pathogens | |
| KR101327798B1 (en) | A Microorganism producing aglucovancomycin | |
| CN104418833A (en) | Antitoxin analogue as well as preparation method and application thereof | |
| JP4755248B2 (en) | Novel antibiotics, bisporides A1, A2 and A3 and bisporides B1, B2a, B2b and B3 and methods for producing these antibiotics | |
| JPWO2006095444A1 (en) | Stemphones and methods for their production |