Method for preparing concentrated culture fluid of active anamorphic fungi species cordyceps with antibiotic activity

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmacology and medicine, and represents a method for preparing a concentrated culture fluid of active anamorphic fungi species P. farinosus, S. militare, V. brongniartii with antibiotic activity, including growth of the fungi Cordyceps in liquid nutrient media (Czapek's medium, cereal infusion, unhopped wort (7%)) in the steady-state environment followed by concentrating of the culture fluid, characterised be the fact that test insects are further infected intra-hemocoel by G. mellonella (introduction of the suspension 0.01 mL into a hemocoel), immersion of larvae into the suspension for 30 seconds, infection of feed with the fungi Cordyceps for preparing the anamorphic virulent forms; and then biotechnological cultures the concentrated culture medium of which has high antibiotic activity is prepared from the mummified and melanised larvae G. mellonella by fungi re-inoculation from the insects on the liquid nutrient media.

EFFECT: invention provides unifying the process of the concentrated culture fluid of the anamorphic fungi Cordyceps.

3 ex, 3 tbl

 

The present invention relates to the field of pharmacology and medicine and can find application in the field of Oncology as drugs with marked antitumor activity, as well as for the treatment of diseases such as bronchitis, pneumonia, tuberculosis, cirrhosis, rheumatoid arthritis, acts as a natural antibiotic, improves health and prolongs life.

A well-known BAD Cordyceps (Cordyceps NSP), using which, the Chinese women's athletics team set world records in 1993-1994 (http://vitolife.ru/product/bad-cordyceps-kordiceps-ot-kompanii-nsp).

The drug Cordycepin from Cordyceps militaris (Sigma-Aldrich) is known as an antibiotic and anticancer drug. Cordyceps has gained popularity in the commercial implementation as "fungus-insect", on its basis, producing various Supplements and drugs. The genus Cordyceps has more than 200, in practice, often use only two types - .sinensis and .militaris. (Vlahova A.A. Entomopathogenic fungi. Leningrad: Nauka, 1974. 260 S.; Koval ET Determinant entomophilous fungi of the USSR. Kiev: Naukova Dumka, 1974. 260 S.; Koval ET Clavicipitaceae fungi of the USSR. Kiev: Naukova Dumka, 1984. - 287 S.). Insect with stromae found in forest litter, it teliomorph stage of the fungus (meiotic sexual sporulation). As a rule, for the destruction of insect and germination stroma need a few months. Along with teliomorph study the th present and anamorphic (asexual) stage, where reproduction of the fungus occurs by mitotic divisions, conidia. Collected in nature insects with stromae affected by fungi (teliomorph stage), do not occur often and are quite expensive commodity. Corporations that produce drugs based on fungi of the genus Cordyceps (Chinese, Japanese, Korean, and others), often used anamorphic stage of development of fungi such as Paecilomyces hepiali C, P.farinosus (Dicks et Fr.), Brown a, Smith (rhynchosporium .sinensis (Berk.) Sacc.); Cephalosporium militare Y.Kabaysi (rhynchosporium .militaris (Fr.).

Famous mushroom .sinensis, parasitic on insects of different orders (Lepidoptera, Coleoptera, and others). This mushroom is harvested in the mountains of Tibet and Nepal, and is used as the basis for the biotechnology mycelium and sclerotia in the production of biologically active substances and medicinal products (Koreneva NV Cordyceps and the immune system: a non-profit Experimental edition. M.: 2009. - 60 S., Illus.).

A known method of cultivation of Cordyceps sinensis (Application Korea No. 20100012923, A01G 1/04; A23K 1/14; A23L 1/28, 2010) includes the cultivation of the fungus in a culture medium containing 1-3% citrus peel, rice bran 3%, glucose 1%, yeast, and getting 2% of culture of Cordyceps sinensis at a temperature of 25-35°C for 4-7 days.

There is a method of cultivation of the fungus Cordyceps (Application of China No. 101215527, C12N 1/14, 2008), in which wild and natural dispute originated on the Tee is Eskom plateau, grafted onto the body of the pupa of the silkworm after artificial germination in the pupa of the silkworm.

The closest analogue is a method of growing Cordyceps sinensis (U.S. Patent No. 6737065, A23K 1/00, A23K 1/175, A23L 1/28, 2004) in broths containing water from washing from grains, such as rice, glutinous rice, barley, wheat, millet, glutinous sorghum ordinary, glutinous millet, hog, and Cuckoo tears with the addition of chromium, selenium and Germany.

The disadvantage of this method are complex and multi-component composition of the nutrient medium, its unbalanced composition of reusable, so the composition of the medium, it is difficult to unify.

The task of the invention is the stability and predictability of results through the use of standard culture media and passages Cordyceps through the test insects.

This object is achieved in that in the method of obtaining a concentrate of the culture fluid anamorphic species of fungi of the genus Cordyceps with antibiotic activity, including the cultivation of fungi of the genus Cordyceps liquid nutrient medium in stationary conditions, followed by concentration of the culture fluid, additionally carry out contamination of the test insects, fungi of the genus Cordyceps to obtain virulent anamorphic forms and then mummified and Melanesia the different insects by reseeding fungi with insects on a standard liquid nutrient medium get biotechnological culture, concentrated culture fluid which has a high antibiotic activity.

The method is as follows.

Example 1. The biological activity of fungi of the genus Cordyceps depends primarily on viral activity. Among fungi of the genus Cordyceps only a few species (.farinosus, .militart, B.brongniartii) can cause mycosis test insects with a high enough % of the deaths. Therefore, carry out the selection of virulent forms after the discovery of the affected Cordyceps insects in ecosystems, using different methods of infection: intralamellar (injection into the hemocoel of 0.01 ml of suspension), the immersion of larvae in suspension for 30 seconds, infected feed. As test insects are the larvae of Galleria mellonella. For infection use of infectious material:

1. .farinosus (rhynchosporium .sinensis) - suspension of powdered Strom, sclerotia and mycelium, the dose of infecting larvae G.mellonella maximum;

2. .militare (rhynchosporium .militarise is the same material as in claim 1, dose of infection of larvae G.mellonella maximum;

3. .brongniartii (rhynchosporium .brongniartii) - suspension, consisting of conidia and mycelium, the dose of infecting larvae G.mellonella maximum (table 1).

Table 1
Infection of larvae G.mellonella different methods for the selection of virulent forms of fungi of the genus Cordyceps (in each variant of the experiment used 30 larvae G.mellonella)
The species name of this fungusThe composition of the infectious materialMaggots G.mellonella (%) with infection by
intravesicularly (injection into the hemocoel larvae 0.01 ml of suspension)immersion in aqueous suspensionfeeding infected feed
P.farinosus (rhynchosporium .sinensis)Stroma + sclerotium + mycelium33,300
C.militare (rhynchosporium .militaris)Stroma + sclerotium + mycelium60,016,60
.brongniartii (rhynchosporium .brongniartii)The sclerotia + mycelium100,043,336,6
Control - water0 00

Fungi of the genus Cordyceps are species average virulent activity, so to defeat them insects the most appropriate place is the forest floor. The period of infection lasts for several months. While infecting insects mushrooms Cordyceps occurs infectious disease that often ends in death of the insect with signs muscardinus (moumifizirovania insects). At the first stage mycosis accompanied by mehanizacija - oxidation of phenolic compounds, catalyzed by the enzyme polyphenoloxidase. One of the prerequisites of mechanisatie should be considered a sharp increase in the blood of insects number of hemocytes containing polyphenoloxidase, directly after exposure of the microorganism into the body cavity (vlahova A.A., vegetable cultures VA protection Mechanisms in insects from fungal pathogens due to virulence factors. In Proc.: Microorganisms in plant protection. - Irkutsk: publishing house of Irkut. University, 1983. - 156 C.). Mehanizacija in insects such as the larvae of a large Bosinney moth (G.mellonella L.), characterized by the presence of black and brown spots that appear a few days before his death. The shape, size, location and number of spots does not depend on the type of fungus, but correlate with the virulence of the strain. So, when the infection is highly virulent strains of Metarhizium anisopliae and .bassiana in which ichino G.mellonella in a large number of registered small brown spots (Loginov E.V. The development of melanosis and density changes of the body in bacterial-fungal mixed infections of larvae big bee the liquidation. In Proc.: Entomopathogenic microorganisms and their use in the national economy. - Irkutsk: publishing house of Irkut. University, 1992. - 121 C.). Brown spots in the cuticle of insects are melanocytes capsule or melanotekite thrombus, where in addition to melanin and sclerotina are proteins and amino acids. As medicinal raw material, for example .sinensis, is the fungus-insect, the value of mummified insects with a large amount of melanin in the cuticle is much higher.

Sign mechanisatie larvae G.mellonella taken as a test for the selection of fungi of the genus Cordyceps. Mummified mehanizirovannye larvae G.mellonella served as the basis for the production of biotechnology crops.

For this, the larvae were put on sterile moist filter paper in Petri dishes and after fouling mushrooms produced reseeding mushrooms in a sterile liquid nutrient medium: čapek (NaNO33 g; KH2PO41 g; MgSO4·7 H2O - 0.5 g; KCl, 0.5 g; FeSO40.01 g; sucrose 30 g; water (distilled) - 1 l) decoctions of cereals (oats (wheat) - 100 g boiled for 1 h in 1 l of water, filtered, added 30 g of sucrose), nikolenka beer wort (1 liter of wort 7-8° Balling). These environments, which are standard for the optimal growth of many microscopic fungi, including entomopathogenic, in this case, fungi of the genus Cordyceps.

The cultivation is carried out in flasks in stationary conditions. After 14 days of cultivation at a temperature of 24-26°C culture liquid (QL) is separated by filtration and concentrated at three times the freeze. For this QOL fungi grown in liquid nutrient medium was separated from the mycelium by filtration, and then was concentrated by freezing cylinder at a temperature of 18°C. After thawing lightest part of QOL were separated. Repeated freezing three times. Thus, QOL was released from the bound water and low molecular weight fractions of fungi.

Example 2. Liquid concentrates QOL anamorphic forms .farinosus, C.militare, .brongniartii tested for antibiotic activity. To do this, in the centre of Petri dishes with sterile agar medium RPA placed sterile standard disk drives firm BioMerieux, impregnated study concentrates QOL fungi (table 2).

Table 2
Antibiotic activity anamorphic species of fungi of the genus Cordyceps
Anamorphic fungi of the genus CordycepsThe zone of growth inhibition of the test cultures of microorganisms (m is)
Sarcina rubra S2Bacillus mycoides B27B. megaterium Bacillus B35Staphylococcus sp. St.34
.farinosus6,60±0,10to 6.43±0,03the ceiling of 5.60±0,215,13±0,49
.militare9,00±0,018,07±0,438,77±0,098,73±0,09
.brongniartii9,00±0,018,83±0,128,82±0,03cent to 8.85±0,09

Example 3. Simultaneously with detection of antibiotic activity anamorphic species of the genus Cordyceps, determined antibiotic activity and teliomorph stages of development of the fungi of this genus. The experiment was carried out by the same method as for anamorphic stage, but the material served alcoholic extracts obtained:

for mushroom .sinensis from Strom, sclerotia and mycelium;

for mushroom .militaris from Strom;

for mushroom .brongniartii from sclerotia and mycelium (table 3).

Table 3
EN Biotechnica activity teliomorph species of fungi of the genus Cordyceps
Teliomorph fungi of the genus CordycepsThe zone of growth inhibition of the test cultures of microorganisms (mm)
Sarcina rubra S2Bacillus mycoides B27B. megaterium Bacillus B35Staphylococcus sp. St.34
.sinensis7,00±0,505,43±0,154,10±0,127,30±0,12
.militarisof 7.60±0,156,70±1,004,63±0,074,90±0,31
.brongniartii6,37±0,097,03±0,037,53±0,126,40±0,10

For fungi of the genus Cordyceps for anamorphic stages of development (concentrated QOL biotech crops), and for teliomorph observed a General pattern (table 1-3), the higher the virulence of the cultures (% death insects) followed by mummification and mechanisatie, the higher antibiotic activity.

The technical effect is to unify the process of obtaining a concentrate of the culture fluid anamorphic species of fungi ro is and Cordyceps. Given the prevalence of drugs on the basis of these fungi, and the fact that they do not always meet the requirements of therapeutic practice, the method allows to obtain biotechnological culture of fungi of the genus Cordyceps on standard nutrient media with stable antibiotic properties.

A method of obtaining a concentrate of the culture liquid active anamorphic species of fungi P. farinosus, S. militare, B. brongniartii with antibiotic activity, including the cultivation of fungi of the genus Cordyceps liquid nutrient media (environment čapek, decoctions grain, nikolenka beer wort (7%)in stationary conditions, followed by concentration of the culture fluid, characterized in that it further implement infection test insects G. mellonella intralamellar (injection into the hemocoel of 0.01 ml of suspension), the immersion of larvae in suspension for 30 seconds, infection of the feed on fungi of the genus Cordyceps to obtain virulent anamorphic forms, and then from mummified and malaysiaboleh larvae of G. mellonella by reseeding with mushrooms insect on liquid nutrient medium get biotechnological culture, concentrated culture fluid which has a high antibiotic activity.



 

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