WO2013100792A1 - Procédé pour accélérer la croissance d'une biomasse bactérienne et supprimer la virulence des bactéries - Google Patents

Procédé pour accélérer la croissance d'une biomasse bactérienne et supprimer la virulence des bactéries Download PDF

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WO2013100792A1
WO2013100792A1 PCT/RU2011/001060 RU2011001060W WO2013100792A1 WO 2013100792 A1 WO2013100792 A1 WO 2013100792A1 RU 2011001060 W RU2011001060 W RU 2011001060W WO 2013100792 A1 WO2013100792 A1 WO 2013100792A1
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dipyridamole
bendazole
papaverine
colonies
enhancers
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PCT/RU2011/001060
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Russian (ru)
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Артур Викторович МАРТЫНОВ
Борис Славинович ФАРБЕР
Софья Борисовна ФАРБЕР
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Martynov Artur Viktorovich
Farber Boris Slavinovich
Farber Sof Ya Borisovna
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Application filed by Martynov Artur Viktorovich, Farber Boris Slavinovich, Farber Sof Ya Borisovna filed Critical Martynov Artur Viktorovich
Priority to EA201300205A priority Critical patent/EA025623B1/ru
Priority to IN1483MUN2014 priority patent/IN2014MN01483A/en
Priority to PCT/RU2011/001060 priority patent/WO2013100792A1/fr
Publication of WO2013100792A1 publication Critical patent/WO2013100792A1/fr

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    • 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
    • C12N1/36—Adaptation or attenuation of cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/02—Local antiseptics
    • 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
    • C12N1/38—Chemical stimulation of growth or activity by addition of chemical compounds which are not essential growth factors; Stimulation of growth by removal of a chemical compound

Definitions

  • the invention relates to medicine, veterinary medicine and biotechnology, namely, the production of genetic engineering and other biotechnological products, and is intended for the treatment of infectious diseases of humans and animals, as well as in biotechnology to enhance the growth of the biomass of microorganisms and the production of medical and veterinary biologics, food additives, probiotics and lactic acid starter cultures, vaccine production.
  • a wide spectrum of biological activity is characterized by stimulants of chemical origin - imidazole, isoquinoline and their derivatives, which are part of the structure of many natural and synthetic compounds that can induce the growth rate of the microbial population [1].
  • the use of enhancers is an important achievement in biotechnological productions; they can increase both the percentage of output of biotechnological protein products and the increase in microbial mass outside the physiological norm by an order of magnitude and higher. So there is a theoretical possibility significantly accelerate the rate of accumulation of microbial mass and the synthesis of protein products by microorganisms.
  • Increased growth and enzymatic activity of microorganisms contribute to an increase in the biomass of cells and, accordingly, metabolites for their further effective application in various sectors of the economy, in particular, in the biotechnological, medical, and pharmaceutical industries.
  • Virulence is a sign not of a species, like pathogenicity, but of strain, i.e. inherent not to the whole species, but to specific strains. Virulence can also be defined as the phenotypic manifestation of the pathogenic genotype of microorganisms. As a quantitative sign of virulence, in contrast to a qualitative one - pathogenicity, it has units of measurement. It is measured by the quantity, i.e., the dose of microorganisms that cause a certain biological effect. It can be:
  • DCL (dosis certae letalis) is an absolutely lethal dose - the minimum amount of the pathogen that causes the death of 100% of laboratory animals taken in the experiment;
  • - DLM dosis letalis minima
  • - LD50 the minimum amount of the pathogen that causes the death of 50% of laboratory animals taken in the experiment (used to measure virulence most often).
  • the type of laboratory animal at which the given dose was determined is always indicated, since the sensitivity of different types of laboratory animals to various microorganisms is different.
  • the method of introducing a culture of microorganisms is also indicated necessarily - intraperitoneally, intramuscularly, intranasally, intravenously.
  • Virulence is a labile sign. It can vary both upward and downward, both in vivo and in vitro. With a maximum reduction in virulence, pathogenic microorganisms can become avirulent, that is, non-virulent, but virulent microorganisms are always pathogenic.
  • Virulence is realized through a series of sequential processes of interaction of microbial cells with cells and tissues of a macroorganism: adhesiveness - the ability to attach to cells;
  • invasiveness the ability to penetrate into cells and adjacent tissues and the formation of biologically active products, including toxins.
  • Adhesion of microorganisms to receptors of sensitive cells of a macroorganism is an essential element of their interaction, since if microorganisms do not adhere, then usually they do not multiply, but are removed from the body.
  • Many microorganisms in the process of evolution have acquired special morphological and chemical structures that provide adhesion. These include villi and adhesins - specific structures (proteins and carbohydrates) on the surface of a microbial cell, corresponding to the receptors of cells of a macroorganism.
  • Microorganisms for example, fungi or bacterial cells
  • exogenous enhancers such as picolinic acid and metal picolinates
  • chromium picolinate enhances the growth of yeast by 30 times (the number of colonies), with the average cell growth index in the presence of stimulants ranging from 0.4 to 0.5 times [ 2 ].
  • a method for suppressing virulence of bacteria by adding a culture medium of effective amounts of phenylpropanoid inhibitors is also known [ 3 ].
  • the disadvantage of this invention is the apparent genotoxicity of the added component and the impossibility of its use in medicine. Although the substance suppressed the expressed virulence factors, it only affected genes, and it was irreversible. Such bacteria, although they lost their virulence factors, became obvious mutants and inherited signs of low virulence in future generations. Disclosure of invention
  • the basis of the invention is the task of developing microbial growth activators that do not contain heavy metals, are non-toxic to humans and animals, do not have a mutagenic and carcinogenic effect and increase the growth of the number of microbial cells by 2 or more times, and also have the ability to suppress virulence microorganisms, which allows them to be used in the treatment of infectious diseases in humans and animals through the use of enhancers before a course of antimicrobial therapy.
  • the problem is solved by adding to the nutrient medium for the cultivation of microorganisms a mixture of microorganism growth activators with proven harmlessness to the human body, which leads to an acceleration of the appearance of the first colonies and an increase in the number of microbial cells by 2-4 times, as well as for the treatment of infectious diseases as inhibitors of virulence of microorganisms before or in parallel with a course of antimicrobial therapy.
  • activators of the accumulation of cyclic adenosine monophosphate such as papaverine, bendazole and dipyridamole, where their mass ratio varies from 1: 100 to 100: 1 and in the range of concentrations in the nutrient medium from 0.0001 g /, are used as activators of the growth of microorganisms. % to 0.1 g /%.
  • papaverine, bendazole and dipyridamole can be both in the form of salts, and in the form of bases, and for therapeutic purposes, they can be administered orally, injection or rectally to a person before using the antibiotic or together with him.
  • the dynamics of the accumulation of microbial mass is important for obtaining nutrients of microbial origin. Allosteric activators of cyclic adenosine monophosphate increase the metabolism of bacteria. As a result of such exposure, the number of microbial cells increases.
  • Table 1 The number of microbial cells of P. aeruginosa when cultured on nutrient agar with the addition of enhancers at a seed dose of 10 6
  • N is the average value of the number of microbial cells of microorganism strains, billion / ml, n is the average deviation, V is the reproduction rate, cells / hour.,% - This is the mass / volume, A is papaverine hydrochloride, B is bendazole, C - dipyridamole ascorbate, * - the difference in indicators is statistically significant (p ⁇ 0.05).
  • the number of microbial cells at 0.1 ⁇ 0.05% of the concentration of enhancer A was (4.2 ⁇ 0.2) - (5.1 ⁇ 0.4) x 10 9 / ml.
  • the number of microbial cells at 0.1 ⁇ 0.05% of the concentration of enhancer B was (4.3 ⁇ 0.3) - (4.6 ⁇ 0.5) x 10 9 / ml.
  • the number of mic of rodent cells at 0.1 ⁇ 0.05% of the enhancer C concentration was (4.1 ⁇ 0.2) - (5.8 ⁇ 0.7) x 10 9 / ml.
  • the number of microbial cells increases to (5.0 - 5.5) x 10 9 / ml.
  • the number of microbial cells at 0.01 ⁇ 0.005% of the concentration of enhancer B was (4.8 ⁇ 0.5) - (5.4 ⁇ 0.3) x 10 9 / ml.
  • the number of microbial cells at 0.01% concentration of enhancer C was (4.8 ⁇ 6.3) - (6.1 ⁇ 0.7) ⁇ 10 9 / ml.
  • the concentration of 0.001% enhancer A promotes the accumulation of microbial cells up to (6.0 - 6.5) x 10 9 / ml.
  • the number of microbial cells at 0.001% enhancer B was (5.2 ⁇ 0.2) - (5.6 ⁇ 0.5) x 10 9 / ml.
  • the number of microbial cells was (3.2 ⁇ 0.2) - (5.2 ⁇ 0.2) x 10 9 / ml.
  • the activity of enhancer A is 0.001 ⁇ 0.0005%, which contributes to the accumulation of microbial cells by a factor of 5–2 compared with other activators growth. That is, the formation of the largest number of microbial cells on nutrient agar was observed at an enhancer concentration of 0.001 ⁇ 0.0005% A and amounted to (5.8 ⁇ 0.4) - (6.3 ⁇ 0.6) billion / ml.
  • results of statistical data processing table. 1. indicate that the differences between the number of microbial cells when using enhancers of different concentrations are statistically significant, which indicates the effectiveness of using enhancers to increase the number of microbial cells.
  • N is the average value of the number of microbial cells of the microorganism, billion / ml, p is the average deviation, V is the rate of reproduction, cells / hour.,% Is mass / volume, A is papaverine hydrochloride, B is bendazole, C is dipyridamole ascorbate, * - the difference in indicators is statistically significant (p ⁇ 0.05).
  • N is the average value of the number of microbial cells of microorganisms, billion / ml, p is the average deviation, V is the reproduction rate, cells / hour.,% Is mass / volume, A is papaverine hydrochloride, B is bendazole, C is dipyridamole. ascorbate, * - The difference in indicators is statistically significant (p ⁇ 0.05).
  • the following indicators of the number of grown microbial cells were obtained when cultured on erythrocyte mass media with the addition of enhancers: at a concentration of 0.1 ⁇ 0.05%, the number of microbial cells was (2.2-3.8) billion / ml independently from P. aeruginosa strain and enhancer species (A, B or C). At a concentration of 0.01 ⁇ 0.005%, the number of microbial cells increases and amounts to (4.1–4.9) billion / ml for all P. aeruginosa strains and all types of enhancers.
  • the number of microbial cells of P. Aeruginosa decreases than at a concentration of 0.01 ⁇ 0.005% and amounts to (3.3 - 4.0) billion / ml. That is, the greatest number of microbial cells is observed when enhancers are added at a concentration of 0.01%. In control, this indicator was (3.2 - 3.5) billion / ml.
  • the largest number of microbial cells on media obtained with erythrocyte mass was observed at an enhancer concentration of 0.001 ⁇ 0.0005% B and was equal to (3.6 ⁇ 0.5) - (4.0 ⁇ 0.2) billion . / ml, and the highest reproduction rate was 1.05 cells / hour. While the smallest number of microbial cells was observed at an enhancer concentration of 0.1 ⁇ 0.05% B and was equal to (2.3 ⁇ 0.3) - (2.6 ⁇ 0.5) billion / ml, and the smallest the reproduction rate was 1, 02 cells / hour.
  • results of statistical data processing table. 3 indicate that the differences between the number of microbial cells when using enhancers A, B or C in a concentration of from 0.001 ⁇ 0.0005% to 0.1 ⁇ 0.05% and control are statistically significant. This indicates the effectiveness of the use of growth stimulants A, B or C of various concentrations to increase the number of microbial cells.
  • N is the average value of the number of microbial cells of microorganisms, billion / ml, p is the average deviation, V is the reproduction rate, cells / hour.,% Is mass / volume, A is papaverine hydrochloride, B is bendazole, C is dipyridamole. ascorbate, * - The difference in indicators is statistically significant (p ⁇ 0.05).
  • the following indicators of the number of grown microbial cells were obtained upon cultivation on media from grain stillage with the addition of enhancers: at a concentration of 0.1 ⁇ 0.05%, the number of microbial cells was (4.2-5.8) billion . / ml regardless of the strain P. aeraginosa and the type of enhancers (A, B or C). At a concentration of 0.01 ⁇ 0.005%, the number of microbial cells increases and amounts to (6.2 - 6.8) billion / ml for all P. aeraginosa strains and all types of enhancers. At a concentration of 0.001 ⁇ 0.0005%, the number of P. aeraginosa microbial cells is less than at a concentration of 0.01 ⁇ 0.005% and amounts to (5.1-5.4) billion / ml. I.e, 11 001060
  • the greatest number of microbial cells is observed when enhancers are added at a concentration of 0.01 ⁇ 0.005% and amounts to (6.2-6.8) billion / ml. In the control, this indicator was equal to (3.2 - 3.5) billion / ml.
  • the number of grown microbial cells using enhancers exceeds 2 times the number of cells that grow on control media, and is higher than the number of microbial cells on the erythrocyte mass.
  • results of statistical data processing table. 4 indicate that the differences between the number of microbial cells when using enhancers A, B or C in a concentration of from 0.001 ⁇ 0.0005% to 0.1 ⁇ 0.05% and control are statistically significant. This indicates the effectiveness of the use of growth stimulants A, B or C of various concentrations to increase the number of microbial cells.
  • N is the average value of the number of microbial cells of microorganisms, billion / ml, p is the average deviation, V is the reproduction rate, cells / hour.,% Is mass / volume, A is papaverine hydrochloride, B is bendazole, C is dipyridamole. ascorbate, * - The difference in indicators is statistically significant (p ⁇ 0.05).
  • the combination of two enhancers A and B at a concentration of 0.01 ⁇ 0.005% increases the number of microbial cells by 3-4 times in comparison with the control and is (7.2-8.2) x 10 9 / ml against (3 , 1-2, 8) x 10 9 / ml in control.
  • the combination of two enhancers A and C at a concentration of 0.01% increases the number of microbial cells by 4 times compared with the control and is equal to (8.3–9.4) x 10 9 / ml versus (3.1–2.8 ) x 10 9 / ml in the control.
  • Approximately the same data are observed with a combination of enhancers B and C.
  • the combination of three growth stimulators GA7B, 1 C ⁇ concentration of 0.01% increases the number of microbial cells by almost 6 times and is (10.5-1 1.8) x 10 9 / ml.
  • the number of microbial cells with the addition of two enhancers A and B at a concentration of 0.001 ⁇ 0.0005% was (9.3-10.4)
  • x 10 9 / ml, with the combined use of two enhancers A and C at a concentration of 0.001 ⁇ 0.0005% was (9.9-10.8) billion / ml
  • the addition of enhancers B and C at a concentration of 0.001 ⁇ 0.0005% was (9.1-9.3) billion / ml. 1060
  • the number of microbial cells was (11.6 -12.6) x 10 9 billion / ml, which is 6.5 times more than in the control. And the highest reproduction rate was 1.12 cells / hour. Whereas the smallest number of microbial cells was observed with a combination of enhancers A and B at a concentration of 0.01%, and the lowest reproduction rate was 1.08 cells / hour.
  • the reproduction rate increases by 1.2 times compared to the control. That is, the number of microorganisms that are cultivated on media from grain stillage with the addition of a combination of enhancers significantly increases compared to the number of bacteria that are cultivated on media obtained from red blood cells with the addition of a combination of enhancers, which indicates the use of media with grain stillage for cultivation of P. aeruginosa.
  • results of statistical data processing table. 5 indicate that the differences between the number of microbial cells when using a combination of enhancers A, B, C in a concentration of from 0.001 ⁇ 0.0005% to 0.1 ⁇ 0.05% and control are statistically significant. This indicates the effectiveness of the use of growth stimulants A, B, C in combination in concentrations from 0.001 ⁇ 0.0005% to 0.1 ⁇ 0.05% to increase the number of microbial cells. How the number of microbial cells changes during cultivation of P. aeruginosa under the influence of a combination of enhancers on erythrocyte mass media is shown in Table. 6.
  • N is the average value of the number of microbial cells of microorganisms, billion / ml, p is the average deviation, V is the reproduction rate, cells / hour.,% Is mass / volume, A is papaverine hydrochloride, B is bendazole, C is dipyridamole. ascorbate, * - The difference in indicators is statistically significant (p ⁇ 0.05).
  • the combination of two enhancers A and B at a concentration of 0.01% increases the number of microbial cells compared to the control by a factor of 2 and is (4.3 - 4.5) x 10 9 / ml versus (2.2 - 3, 1) x 10 9 / ml in the control.
  • the combination of two enhancers A and C increases the number of microbial cells to (4.1- 4.9) x 10 9 / ml.
  • the number of microbial cells also practically changes with the addition of a combination of two enhancers B and C.
  • the combination of three growth stimulants A, B and C at a concentration of 0.01% increases the number of microbial cells by 3 times and amounts to (5.3 - 5, 8) billion / ml.
  • the number of cells with the addition of two enhancers A and B at a concentration of 0.001 ⁇ 0.0005% is (4.5-4.7) x 10 9 / ml, with a combination of two of enhancers A and C in the same concentration, the number of cells was (3, 8-4, 1) x 10 9 / ml, with the addition of enhancers B and C at a concentration of 0.001%, the number of cells was (3.7-4.0) x 10 9 / ml.
  • the number of cells was (6.2-6.4) x 10 9 / ml, which is 3 times more than in the control.
  • the highest reproduction rate was 1.08 cells / hour. with the addition of three stimulants A, B and C at a concentration of 0.001 ⁇ 0.0005%.
  • the number of microorganisms cultivated on media obtained from erythrocyte mass with the addition of a combination of enhancers significantly increases, which indicates the advisability of using these media for the cultivation of P. aeruginosa microorganisms.
  • Figure 7 shows the exposure of the appearance of P. aeruginosa colonies on different media without growth stimulators.
  • enhancers influenced the appearance of colonies (Table 7). At a concentration of 0.1 ⁇ 0.05% A, Pseudomonas aeruginosa colonies appeared after 10 hours of incubation, whereas on control media after 12-14 hours. A concentration of 0.01 ⁇ 0.005% A decreased the cultivation period and colonies of microorganisms were recorded after 6-8 hours. The addition of 0.001% concentration of stimulant A to the medium facilitated the appearance of colonies after 7 hours. There were no particular differences in incubation time between enhancer concentrations of 0.01 ⁇ 0.005% and 0.001 ⁇ 0.0005% for the appearance of colonies. The difference in the number of colonies between growth stimulants A, B, and C at different incubation periods did not significantly differ.
  • Figure 9 shows how growth stimulants at a concentration of 0.01% A affect the appearance of colonies on various nutrient media (nutrient agar, erythrocyte mass, and grain bard).
  • Table 9. Exposition of the appearance of colonies on nutrient media with the addition of enhancers at a concentration of 0 , 01 ⁇ 0.005% A at a sowing dose of 10 '
  • Example 2 Reduction of virulence of P. aeruginosa under the influence of growth enhancers on the example of the suppression of adhesive properties
  • adhesion of microorganisms is the first stage of colonization, the main and determining factor of their virulence and pathogenicity.
  • adhesins microbes recognize receptors on cell membranes, attach to them and colonize various surface structures of the cell wall.
  • the ability of bacteria to adhesion and colonization of surfaces is fixed by natural selection. This function is necessary for bacteria with saprophytic existence. For example, legionella actively attach to the surface of cyanobacteria, cholera vibrios actively colonize zooplankton, the chitin of which they use as a food source and stimulates the multiplication of cholera vibrios [ 4 ].
  • Adhesion of a bacterial pathogen can be carried out to the components of the extracellular matrix — fibronectin, collagen, laminin, etc.
  • Matrix proteins have an RGD sequence with which integrins of the cell surface interact.
  • extracellular matrix proteins contribute to the adhesion of bacteria to the target cells of the host.
  • the adhesion of bacteria to such proteins is specific the nature and each pathogen implements this opportunity in its own way. For the manifestation of the pathogenicity of some bacteria, their interaction with matrix proteins is critical.
  • adhesins are special organelles [ 6 ]. Many pathogenic microorganisms are able to penetrate the host cells and proliferate actively in them. Adherent molecules called invasinams are used to penetrate bacteria into cells. The most common mechanism involves the activation of signals in the host cell, allowing the invasion of bacteria by triggering normal cellular responses.
  • adhesion indices differed from control indices. Strains that were moderately adhesive retained these properties upon cultivation with growth stimulators separately. Separate use of enhancers at a concentration of 0.001 ⁇ 0.0005% reduced the adhesive activity of Pseudomonas aeruginosa strains to (2.4 ⁇ 0.4) - (2.7 ⁇ 0.4), and the strains became low-adhesive.
  • Patient N 42 years old, suffering from an open form of pulmonary tuberculosis caused by multidrug-resistant mycobacterium tuberculosis.
  • the first and second line anti-TB drugs were ineffective (they used traditional therapy according to WHO criteria: isoniazid (H), rifampicin (R), pyrazinamide (Z), streptomycin (F)).
  • the patient was repeatedly operated on.
  • the patient was prescribed intravenous drip papaverine 1% 2 ml, dibazole 2% 2 ml and dipyridamole 0.5% 4 ml in one dropper per 400 ml of 0.9% sodium chloride solution intravenously dropwise once a day.
  • Patient C 70 years old, was hospitalized with a diagnosis of open tuberculosis of the upper lobe of the right lung, destruction +, mycobacteria +, M +, +, resistance +.
  • the patient received treatment with isoniazid (H), rifampicin (R), pyrazinamide (Z), streptomycin (F), which was ineffective.
  • the patient was given the same regimen (H, R, Z, F), but papaverine 1% 2 ml, dibazole 2% 2 ml and dipyridamole 0.5% 4 ml in one dropper per 400 ml were added 1 time per day. 0.9% sodium chloride solution is administered intravenously slowly once a day.
  • the invention relates to microbiology, namely biotechnology, pharmacy and medicine and can be used to accelerate the growth of biomass probiotics, genetically engineered drugs, yeast, vaccine strains of microorganisms, lactic acid starter cultures, and can also be used to suppress the virulence of bacteria and fungi in the treatment of infectious diseases of humans and animals.
  • Vityuk N.V. Analysis of the structure-activity relationship of clonidine-like imidazolines based on the above description of the molecular structure [Text] / N.V. Vityuk // Chem. journal - 1997.- t.31. - JY ° 4. - S.44-47
  • Pseudomonas aeruginosa infection in a trauma hospital abstract. dis. to receive scientific Candidate of medical sciences: special. 07/03.00 "GuPkrobyulopya” / B. I. Aslanov. - St. Moscow, 2001 .-- 24 p.

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Abstract

L'invention concerne la biotechnologie et la médecine. Le procédé pour accélérer la croissance de la biomasse bactérienne et supprimer la virulence des bactéries comprend l'utilisation en tant qu'inhibiteurs de la virulence des micro-organismes des inducteurs de phosphorylation des protéines intracellulaires dont font partie des activateurs d'accumulation d'adénosine-monophosphate cyclique tels que les sels ou les bases de papavérine, de dipyridamole, de bendazole et de dipyridamole. On utilise en tant que accélérateurs à faible poids moléculaire de la croissance des micro-organismes un mélange des inducteurs de phosphorylation des protéines intracellulaires. On utilise en tant qu'activateurs d'accumulation d'adénosine-monophosphate cyclique des sels ou des bases de papavérine, de dipyridamole, de bendazole et de dipyridamole dans des concentrations déterminées. Pour supprimer la virulence des bactéries, le malade infectieux se fait proscrire 1 à 10 jours avant la prescription d'un antibiotique ou parallèlement à celui-ci par voie parentérale, pérorale, rectale ou par application à la région lésée.
PCT/RU2011/001060 2011-12-28 2011-12-28 Procédé pour accélérer la croissance d'une biomasse bactérienne et supprimer la virulence des bactéries WO2013100792A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
EA201300205A EA025623B1 (ru) 2011-12-28 2011-12-28 Способ ускорения прироста бактериальной биомассы и подавление вирулентности бактерий
IN1483MUN2014 IN2014MN01483A (fr) 2011-12-28 2011-12-28
PCT/RU2011/001060 WO2013100792A1 (fr) 2011-12-28 2011-12-28 Procédé pour accélérer la croissance d'une biomasse bactérienne et supprimer la virulence des bactéries

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PCT/RU2011/001060 WO2013100792A1 (fr) 2011-12-28 2011-12-28 Procédé pour accélérer la croissance d'une biomasse bactérienne et supprimer la virulence des bactéries

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Cited By (1)

* Cited by examiner, † Cited by third party
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WO2019098869A1 (fr) * 2017-11-15 2019-05-23 Борис Славинович ФАРБЕР Composition pharmaceutique pour stimuler la division des cellules souches et supprimer la virulence des bactéries

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US20090005340A1 (en) * 2005-06-15 2009-01-01 Medimush A/S Bioactive Agents Produced By Submerged Cultivation of a Basidiomycete Cell
US20110262988A1 (en) * 2008-11-17 2011-10-27 Designer Energy Ltd. Methods and compositions for enhanced bacterial hydrolysis of cellulosic feedstocks

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090005340A1 (en) * 2005-06-15 2009-01-01 Medimush A/S Bioactive Agents Produced By Submerged Cultivation of a Basidiomycete Cell
US20110262988A1 (en) * 2008-11-17 2011-10-27 Designer Energy Ltd. Methods and compositions for enhanced bacterial hydrolysis of cellulosic feedstocks

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019098869A1 (fr) * 2017-11-15 2019-05-23 Борис Славинович ФАРБЕР Composition pharmaceutique pour stimuler la division des cellules souches et supprimer la virulence des bactéries
US11191767B2 (en) 2017-11-15 2021-12-07 Boris Slavinovich FARBER Pharmaceutical composition for stimulating stem cell division and suppressing bacterial virulence

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EA025623B1 (ru) 2017-01-30
EA201300205A1 (ru) 2014-11-28
IN2014MN01483A (fr) 2015-04-17

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