WO2001086287A1 - Procede de criblage de compose a activite antimicrobienne sur un micro-organisme pathogene infectant un organisme ayant acquis un mecanisme d'immunite, et procede d'evaluation correspondant - Google Patents

Procede de criblage de compose a activite antimicrobienne sur un micro-organisme pathogene infectant un organisme ayant acquis un mecanisme d'immunite, et procede d'evaluation correspondant Download PDF

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Publication number
WO2001086287A1
WO2001086287A1 PCT/JP2001/003945 JP0103945W WO0186287A1 WO 2001086287 A1 WO2001086287 A1 WO 2001086287A1 JP 0103945 W JP0103945 W JP 0103945W WO 0186287 A1 WO0186287 A1 WO 0186287A1
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Prior art keywords
organism
immune mechanism
pathogenic microorganism
test sample
silkworm
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PCT/JP2001/003945
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English (en)
Japanese (ja)
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Kazuhisa Sekimizu
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Sekimizu, Nobukazu
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Priority to AU2001256708A priority Critical patent/AU2001256708A1/en
Priority to JP2001583180A priority patent/JPWO2001086287A1/ja
Publication of WO2001086287A1 publication Critical patent/WO2001086287A1/fr

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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
    • G01N33/5008—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
    • G01N33/5082—Supracellular entities, e.g. tissue, organisms
    • G01N33/5085—Supracellular entities, e.g. tissue, organisms of invertebrates
    • 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
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/195—Assays involving biological materials from specific organisms or of a specific nature from bacteria
    • G01N2333/21—Assays involving biological materials from specific organisms or of a specific nature from bacteria from Pseudomonadaceae (F)
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/195—Assays involving biological materials from specific organisms or of a specific nature from bacteria
    • G01N2333/305—Assays involving biological materials from specific organisms or of a specific nature from bacteria from Micrococcaceae (F)
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
    • G01N2333/43504—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans from invertebrates
    • G01N2333/43552—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans from invertebrates from insects
    • G01N2333/43578—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans from invertebrates from insects from silkworm

Definitions

  • This study aims to screen for compounds that have antimicrobial activity against JSi microorganisms by using organisms that have only the innate immunity mechanism as well as to infect organisms that have an acquired immunity mechanism.
  • the present invention relates to a method for evaluating antibacterial activity against microorganisms using a living organism having only a natural immune mechanism.
  • an infection model using an organism having only the innate immunity mechanism could be a model for microbial infection of an organism having the adaptive immunity mechanism. Therefore, it was also unclear whether an infection model using an organism having only the innate immunity mechanism could be used in screening an antibacterial agent for treating a microbial infection in an organism having an adaptive immunity mechanism. .
  • the present invention has been made in view of such circumstances, and an object thereof is to provide a model of microbial infection in which an organism having only the natural immunization mechanism is used as an Icheon-based organism, and to provide a microbial infection in an organism having an acquired immune mechanism.
  • the present invention also provides a method for screening a compound exhibiting a pharmacological activity against a pathogenic microorganism that infects an organism having an acquired immune mechanism, and a method for evaluating the antibacterial activity, using these infection models.
  • Target In a preferred embodiment of the present investigation, as the infection model, it squats to insects.
  • an organism that can be infected by a gram-positive pathogenic microorganism is used as the infection model.
  • the present invention also aims at reducing the amount of experiment space and experiment space in screening antibacterial agents and evaluating antibacterial activity.
  • the present inventors have conducted intensive studies to solve the above-mentioned problems, and as a result, silkworms (arthropods, mandibles) whose generations have been changed quickly, can be easily bred in a laboratory, and genetic analysis is progressing Submonas, winged insects, belonging to the order Lepidoptera). Bombyx larvae have large larvae, so injection of pathogens and drugs is relatively small compared to small organisms such as C. e7e /? Extremely easy
  • the present inventors have attempted to develop an infection model of a pathogenic microorganism using silkworm larvae.
  • the present inventors examined whether silkworm larvae are useful as antibacterial agent evaluation systems in individuals.
  • injection of live Staphylococcus aureus or Pseudomonas aeruginosa bacteria into the blood of the silkworm larva killed most of the larvae in a short period of time.
  • the autoclaved Staphylococcus aureus was injected, no death of the silkworm larva was observed.
  • E. coli was injected, most of the silkworm larvae survived even 5 days after the injection.
  • Staphylococcus aureus After injection of Staphylococcus aureus, blood and tissues of silkworm larvae were collected over time, and it was confirmed that Staphylococcus aureus was growing. Immunostaining using anti- & aureus antibodies suggested that S. aureus was growing in the mid-gut epithelium. These results indicate that injection of B. aureus or Pseudomonas aeruginosa into the silkworm larvae kills the silkworm larvae.
  • the present invention provides a world in which the efficacy of an antibacterial agent against pathogenic microbial infections in organisms having only the innate immunity mechanism and the efficacy of antimicrobial agents against pathogenic microbial infections in organisms having an acquired immune mechanism have been demonstrated. This is the first example. Therefore, the present invention is also the first in the world to succeed in developing a system for evaluating anti-bacterial activity against pathogenic microorganisms that infect organisms having an acquired immune system by using organisms that possess only the innate immune system. Is also an example.
  • the present invention relates to a screening of a compound having an antibacterial activity against pathogenic microorganisms infecting an organism having an adaptive immunity mechanism using an organism having only an innate immune mechanism, and a review of the antibacterial activity iilli. Is
  • test sample improves the infectious symptoms of an organism having only the natural immunological mechanism or the degree of survival as compared to the case where no test sample is administered (control) Deciding whether or not
  • the creature belonging to the insects is a larva, the method described in (5)
  • the pathogenic microorganism that infects the animal having an immune mechanism is selected from the group consisting of 1 ⁇ 2 Staphylococcus aureus, Pseudomonas aeruginosa, Cholera and pathogenic Escherichia coli. From (1)
  • the present invention provides a method for screening a compound having anti-microbial activity against an organism having an acquired immune mechanism by using an organism having innate immunity and a method for naturally immunizing the antibacterial activity.
  • the present invention provides a method for evaluation using living organisms.
  • a pathogenic microorganism and a test substance are administered to an organism that has only the natural immune system (-r. (A)).
  • ⁇ ⁇ Natural immune system Means an immune host defense mechanism (innate immunity mechanism) that does not depend on an adaptive immunity (acquired immunity) mechanism.
  • Vertebrate animals have an adaptive immunity mechanism that protects the body by using molecules such as antibodies that specifically recognize invaders against invading pathogens, while invertebrates and plants have such an adaptive immunity mechanism. do not do.
  • the “organism having only the innate immunity mechanism” in the present invention is, in other words, an invertebrate and a plant having no acquired immunity mechanism.
  • the organism to which the pathogenic microorganism is administered is not particularly limited as long as it has only the innate immunity mechanism, but an organism belonging to insects is a preferred example.
  • the term "insects" refers to a net of the arthropod phylum, and is composed of four subclasses of bryozoan, coleopteran, wingless biecta, and lepidoptera Means a leash.
  • the organism that succumbs to the worms used in the present invention is not particularly limited.
  • Larvae are preferred for convenience of handling. Larvae include, but are not limited to, larvae of the order Lepidoptera (including geese) and Coleoptera (including the beetle).
  • the larvae are preferably large.
  • the term "large larva” refers to a larva with a body length of 1 cm or more.
  • organisms other than bizoids include arthropods other than insects such as spiders and scorpions, slaughtered animals such as slugs and rodents, annelids such as earthworms, starfish, and ephemerides such as starfish.
  • arthropods other than insects such as spiders and scorpions
  • slaughtered animals such as slugs and rodents
  • annelids such as earthworms, starfish, and ephemerides such as starfish.
  • Examples include cutaneous animals, nematodes of nematodes and roundworms, nematodes such as hydra, sea anemones and jellyfish, and all plants such as rice and radish. These organisms can also be used for the present invention.
  • Organisms that possess only the innate immune system include those infected by gram bacteria, those infected by gram positive bacteria, and those infected by both.
  • a therapeutic agent for human infections caused by Gram-positive bacteria such as Staphylococcus aureus
  • those infected by Gram-positive bacteria must be used.
  • Icheon will be.
  • Silkworm used in this example Larvae are infected not only by Gram-negative bacteria but also by Gram-positive bacteria, Staphylococcus aureus, and can be suitably used for the development of these antibacterial agents.
  • pathogenic microorganism means a microorganism capable of infecting a host and causing a disease.
  • a pathogenic microorganism that infects at least one kind of organism having an acquired immune mechanism is used. From the viewpoint of the development of antibacterial agents against microbial infections in humans, it is preferable to use pathogenic microorganisms that infect humans.
  • Pathogenic microorganisms include both gram-negative and gram-positive bacteria.
  • Gram-negative bacteria that can be ffl suitable for this development include, for example, Pseudomonas aeruginosa, cholera, and pathogenic Escherichia coli (0-157).
  • Gram-positive bacteria include, for example, Staphylococcus aureus However, it is not limited to these.
  • test sample to be administered to the host organism is not particularly limited, and a desired sample to be evaluated for antibacterial activity is used.
  • the test samples e.g., cell extracts, the cell culture;, products of fermenting microorganisms, marine organism extracts, plant extracts, ⁇ made or crude proteins, peptides, non-peptide compounds, synthetic low molecular compound And natural compounds, but are not limited thereto.
  • the pathogenic microorganism and the test sample can be administered to the host by, for example, intraperitoneal administration, injection into the blood, addition to feed (feed), injection into the intestine, and the like.
  • Pathogenic microorganisms The dose of the test sample to the host varies depending on the pathogenic microorganism, the host, and the type of the test sample. In general, the pathogenic microorganism is administered as a dilution from the highest cultivable bacterial solution to about 1 / 10,000 dilution. In the case where a larva of an organism belonging to an insect is used as a host, for example, about 0.05 ml of a bacterial solution may be injected into the blood width from the leg.
  • test sample determine the river ⁇ minimum that kills the host ⁇ , and administer a smaller amount.
  • pathogenic microorganism fc 'main and the type of the test sample, and the like.
  • the pathogenic microorganisms and the test subject are examined for the sensitivity or survival of organisms exhibiting the innate immune mechanism to which the sample was administered (see (b)).
  • Infectious symptoms to be detected include, for example, 1) an increase in the number of pathogenic microorganisms in the host individual, 2) a decrease in the weight of the host or inhibition of the increase in the weight of the host, 3) a decrease in the amount of antibacterial substances in the blood of the host, and 4) a host. ⁇ deficiency of immune function, ⁇ reduction of various enzyme activities in host body fluids and internal organs.
  • the host is a larva of an insect, for example, it may be detected that the larva does not molt to an older larva or does not become a pupa or an adult.
  • the degree of survival of the host may be detected in addition to the above infection symptoms.
  • the degree of survival includes, for example, survival rate and survival period.
  • the infectious symptom of the organism having the immune system is improved or survived, as compared with the case where the test sample is not administered (control).
  • Select the compound that improves the degree step (c)).
  • the test sample improves the infectious disease state of the organism having the innate immune mechanism as compared with the case where the test sample is not administered (control).
  • the test sample modifies the infectious symptoms of the host organism or improves the degree of survival as compared to the control
  • the test sample is: f It can be determined that the antimicrobial activity against the pathogenic microorganism administered to the main organism is high, while the test sample injected does not improve the infection symptoms of the host organism or survive compared to the control. If the concentration is not increased, it can be determined that the test sample has no antibacterial activity against the pathogenic microorganisms administered to the host organism. Samples determined to have antimicrobial activity are good candidates for antimicrobial activity against pathogenic microorganisms injected into the main organism. Simple explanation of the figure
  • FIG. 1 is a diagram showing the survival rate of silkworm larvae injected with S. aureus, P. aeruginosa, and E. coli.
  • Staphylococcus aureus 4220, Smith, MSSA, MRSA
  • Pseudomon as aeruginosa S24
  • Escherichia coli K12-3, W3110, NIHJ
  • 0.05 ml 3 ⁇ 10 7 cells
  • FIG. 2 is a diagram showing the growth of Staphylococcus aureus in a silkworm larva.
  • Staphylo coccus aureus (MSSA) culture broth was diluted 10-fold with 0.6% NaCl, and 0.05 ml (3 x 10 7 cells) of the diluted culture was injected into the silkworm larvae.
  • And tissue (B) were collected, suspended in 0.6% NaCl, applied to a mannitol medium, cultured at 37 ° C overnight, and the number of colonies that appeared was counted.
  • Figure 3 is a micrograph showing the presence of Staphylococcus aureus in the midgut of the silkworm larva. 0.9% NaCl (A) or yellow globule i (MSSA) (3 x 10 7 cell s) (B) was injected into the silkworm larva, and after 40 hours, a paraffin-wrapped woven section of the paraffin of the submucosa was prepared. Contact with a S. aureus antibody was performed by the photoantibody method. The left side of the figure is the body surface and the right side is the inside of the intestine.
  • A NaCl
  • MSSA yellow globule i
  • FIG. 4 is a graph showing the effects of various antibacterial substances on infection death of silkworm larvae by Staphylococcus aureus.
  • Staphylococcus aureus (3 ⁇ 10 7 cells / 0.05 ml) was injected into 10 young silkworms and further injected with the antibiotic ft (0.2 mg / 0.05 ml), and thereafter the number of surviving animals was counted temporarily.
  • Antibiotics i were ampicillin, oxasillin, and vancomycin.
  • the green erythrocyte W RN4220 that was collected was distributed by Kawahira Tenten University Hiramatsu.
  • Staphylococcus aureus MSSA and MRSA clinical isolates from Kyushu University Hospital were used (Akimitsu, N., et al. 1999. Antimicrob Agents Chemother 43: 3042-3043.).
  • Yellow budu bulb [Smith strain and large intestine i NIHJ strain were isolated from Research Institute for Fine Materials Chemistry, Dr. Hamada]. Recitation (S24), Dai I WW3110 shares and K12-3 shares studied A laboratory stock was used.
  • Staphylococcus aureus was cultivated and confirmed on agar medium in Mannite salt medium (Eiken Chemical Co., Ltd.), Pseudomonas aeruginosa in NAC medium (Eiken Chemical Co., Ltd.), and Escherichia coli on D0C medium (Eiken Chemical Co., Ltd.). . These inverted single colonies were used overnight in LB liquid medium.
  • fertilized eggs of silkworm larvae were purchased from Japan Sericulture Industry Co., Ltd. and reared with artificial feed (silk mate: Japan Sericulture Industry Co., Ltd.) at room temperature.
  • Example 1 Infection and death of silkworm larvae by Staphylococcus aureus and Pseudomonas aeruginosa
  • Staphylococcus aureus and Pseudomonas aeruginosa are the causative agents of F1 opportunistic infection in humans.
  • the present inventors examined whether these bacteria could infect silkworm larvae by infection.
  • 0.05 ml of a bacterial solution or an antibacterial substance solution of Staphylococcus aureus and Pseudomonas aeru was injected into the abdominal leg of the fifth-instar silkworm larvae, and the bleeding was stopped for 10 seconds by finger pressure.
  • the injection needle used was 27G X 3/4 (Termo Corporation), and the injection cylinder was 1 ml (Termo Corporation). The number of surviving individuals over time after the injection was examined (FIG. 1).
  • the tail limb of the silkworm larva injected with the bacteria is cut, the body fluid is collected, diluted with 0.6% NaCl, spread on Mannit medium (Eiken Chemical Co., Ltd.), and cultured at 37 ° C overnight. The number of colonies that appeared was counted, and the number of bacteria in the silkworm body fluid was calculated.
  • the silkworm larvae were laparotomized on a paper tube, the body fluid was removed, suspended in 0.9% NaCl, spread on Mannitol medium, and the number of colonies that appeared was counted. The number of bacteria in the tissue was calculated.
  • the volume of the fluid and the tissue of the silkworm larva were calculated as 1.5 ml and 1 ml, respectively.
  • Figure 3 is a histological image of the silkworm larvae's midgut cut perpendicular to the body axis 40 hours after injection of S. aureus.
  • the silkworm larvae injected with Staphylococcus aureus clear fluorescence was observed in the midgut epithelium. This fluorescence was not observed in larvae that were not injected with Staphylococcus aureus ( Figure 3A) or without primary antibody (data not shown).
  • the present inventors investigated whether the death of Bombyx mori larva infection by Staphylococcus aureus could be suppressed by antibiotics. After injection of the clinical isolate of B. aureus into silkworm larvae, ampicillin, oxacillin and vancomycin were injected, and the number of surviving silkworm larvae was counted over time.
  • IC5 () for infected silkworm larvae 5 ⁇ 10 6 S. aureus were injected into the silkworm larva blood, and then 0.05 ml of various concentrations of antimicrobial solutions were injected. Four days after the injection, the concentration of the antibacterial substance at which the number of surviving individuals was half was determined. The IC 5 (1 value was calculated assuming that the body fluid of the silkworm larva was 1.5 ml.
  • LD5 () for the silkworm larva was injected with 0.05 ml of various concentrations of antibacterial solutions to 5 larvae, and one day after the injection The concentration at which half of the larvae die in the eye.
  • the infection model of the present invention can be used as a model for infection of various pathogens to organisms having an acquired immune mechanism, including humans, and is useful for screening antibacterial agents for infectious diseases caused by these pathogens.
  • the infectious model of the present invention can be expected to contribute to the efficient development of antibacterial agents that can be used for human clinical application by using the infectious model as a pre-stage of pathogenic microorganism infection experiments using mammals.
  • the silkworm infection model is effective for the development of antibacterial activity against opportunistic infections caused by Staphylococcus aureus, for example, because it is infected by gram-positive pathogenic bacteria.
  • the use of the infection model of the present invention greatly reduces acquisition costs, breeding costs, and experimental space per individual in drug screening, unlike the conventional case of using a mammal. It becomes possible. For example, (filtering the 1 air fill evening one, and 2 to keep the temperature and humidity constant, is necessary) 1000 mice SPF environment space required for breeding in is an approximately 25 m 2 In addition, backup facilities such as a cage washing room and an autoclave room are required.
  • the silkworm infection model of the present invention is extremely easy to inject pathogens and drugs compared to small organisms such as C.e7e /] s, and can be said to be suitable for evaluating antibacterial drugs against pathogens.
  • the infection model of the present invention is also effective for elucidating the innate immunity mechanism against pathogen infection at the molecular level using genetic techniques.

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Abstract

Selon l'invention, on examine si oui ou non les larves de vers à soie possédant seulement un mécanisme d'immunité naturelle sont utiles en tant que système d'évaluation d'un agent antimicrobien. On trouve que les larves de vers à soie meurent d'infection après injection de ∫i⊃Micrococcus flavus∫/i⊃ ou de ∫i⊃Pseudomonas aeruginosa∫/i⊃. Les effets d'agents antimicrobiens sur des larves de vers à soie s'accordent de manière surprenante avec les efficacités cliniques de ces médicaments sur l'homme, c'est à dire sur un organisme ayant acquis un mécanisme d'immunité.
PCT/JP2001/003945 2000-05-11 2001-05-11 Procede de criblage de compose a activite antimicrobienne sur un micro-organisme pathogene infectant un organisme ayant acquis un mecanisme d'immunite, et procede d'evaluation correspondant WO2001086287A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
AU2001256708A AU2001256708A1 (en) 2000-05-11 2001-05-11 Method of screening compound having antimicrobial activity on pathogenic microorganism infecting organism having acquired immune mechanism by using organism having natural immune mechanism alone, and method of evaluating the antimicrobial activity by using organism having natural
JP2001583180A JPWO2001086287A1 (ja) 2000-05-11 2001-05-11 獲得免疫機構を有する生物に感染する病原微生物に対し抗菌活性を有する化合物を自然免疫機構のみを有する生物を利用してスクリーニングする方法、および該抗菌活性を自然免疫機構のみを有する生物を利用して評価する方法

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JP2000-177565 2000-05-11
JP2000177565 2000-05-11
JP2001081971 2001-03-22
JP2001-81971 2001-03-22

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WO2005116269A1 (fr) * 2004-05-26 2005-12-08 Genome Pharmaceuticals Institute Co., Ltd. Procédé de criblage d'un échantillon ayant une activité antivirale contre un virus ayant l'aptitude à infecter un organisme présentant un mécanisme immunitaire acquis grâce à l'utilisation d'un organisme individuel, ou de sa cellule mise en cu
JP2008039415A (ja) * 2006-08-01 2008-02-21 Genome Soyaku Kenkyusho:Kk 薬剤の副作用を緩和する活性を有する物質の評価方法及びスクリーニング方法、並びに、これらの方法により同定された物質を有効成分とする副作用緩和剤
JP2008128819A (ja) * 2006-11-21 2008-06-05 Genome Soyaku Kenkyusho:Kk 花粉症に対する予防又は治療作用を有する物質の評価方法及びスクリーニング方法、並びに、花粉症の予防又は治療のための薬剤及びその製造方法
WO2008126905A1 (fr) * 2007-04-10 2008-10-23 Genome Pharmaceuticals Institute Co., Ltd. Procédé d'évaluation et procédé de sélection de substance ayant une action d'activation et de suppression de l'immunité innée, d'agent et de produit alimentaire destinés à l'activation et à la suppression du mécanisme de l'immunité innée et
JP2009058500A (ja) * 2007-08-06 2009-03-19 Genome Soyaku Kenkyusho:Kk 血糖値を降下させる物質の評価方法、スクリーニング方法及び製造方法
JP2009219356A (ja) * 2008-03-13 2009-10-01 Genome Soyaku Kenkyusho:Kk 被検対象物の病原性微生物による汚染度を評価する方法
WO2011148959A1 (fr) * 2010-05-25 2011-12-01 株式会社ゲノム創薬研究所 Composé peptidique cyclique inédit, son procédé de production, agent anti-infectieux, fraction contenant un antibiotique, antibiotique, procédé de production d'antibiotiques, microorganisme produisant un antibiotique et antibiotique ainsi produit
JP2012005480A (ja) * 2010-05-25 2012-01-12 Genome Soyaku Kenkyusho:Kk 抗生物質産生微生物及びそれが産生した抗生物質
JP2012005481A (ja) * 2010-05-25 2012-01-12 Genome Soyaku Kenkyusho:Kk 抗生物質含有画分、その抗生物質及びその抗生物質の製造方法

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WO2015053419A1 (fr) * 2013-10-08 2015-04-16 그린테코 주식회사 Composition de ver à soie, et dispositif pour injecter une solution d'injection dans des larves
CN107179364B (zh) * 2017-05-26 2019-08-13 桂林理工大学 一种利用高效液相测定沸石分子筛抗菌剂抗菌机理的方法

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