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WO2024127496A1 - METALLO-β-LACTAMASE INHIBITOR AND USE THEREOF - Google Patents

METALLO-β-LACTAMASE INHIBITOR AND USE THEREOF Download PDF

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Publication number
WO2024127496A1
WO2024127496A1 PCT/JP2022/045833 JP2022045833W WO2024127496A1 WO 2024127496 A1 WO2024127496 A1 WO 2024127496A1 JP 2022045833 W JP2022045833 W JP 2022045833W WO 2024127496 A1 WO2024127496 A1 WO 2024127496A1
Authority
WO
WIPO (PCT)
Prior art keywords
yeast
lactic acid
metallo
multidrug
negative bacteria
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/JP2022/045833
Other languages
French (fr)
Japanese (ja)
Inventor
治 徳野
雅寛 中西
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Nihon Sizen Hakkoh Co Ltd
Original Assignee
Nihon Sizen Hakkoh Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Nihon Sizen Hakkoh Co Ltd filed Critical Nihon Sizen Hakkoh Co Ltd
Priority to PCT/JP2022/045833 priority Critical patent/WO2024127496A1/en
Priority to JP2024563811A priority patent/JPWO2024127496A1/ja
Priority to TW112104841A priority patent/TW202423405A/en
Publication of WO2024127496A1 publication Critical patent/WO2024127496A1/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L11/00—Pulses, i.e. fruits of leguminous plants, for production of food; Products from legumes; Preparation or treatment thereof
    • A23L11/50—Fermented pulses or legumes; Fermentation of pulses or legumes based on the addition of microorganisms
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L17/00—Food-from-the-sea products; Fish products; Fish meal; Fish-egg substitutes; Preparation or treatment thereof
    • A23L17/60—Edible seaweed
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    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L19/00—Products from fruits or vegetables; Preparation or treatment thereof
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L19/00—Products from fruits or vegetables; Preparation or treatment thereof
    • A23L19/10—Products from fruits or vegetables; Preparation or treatment thereof of tuberous or like starch containing root crops
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L29/00—Foods or foodstuffs containing additives; Preparation or treatment thereof
    • A23L29/20—Foods or foodstuffs containing additives; Preparation or treatment thereof containing gelling or thickening agents
    • A23L29/206—Foods or foodstuffs containing additives; Preparation or treatment thereof containing gelling or thickening agents of vegetable origin
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
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    • A23L29/00—Foods or foodstuffs containing additives; Preparation or treatment thereof
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    • A23L29/206—Foods or foodstuffs containing additives; Preparation or treatment thereof containing gelling or thickening agents of vegetable origin
    • A23L29/256—Foods or foodstuffs containing additives; Preparation or treatment thereof containing gelling or thickening agents of vegetable origin from seaweeds, e.g. alginates, agar or carrageenan
    • A—HUMAN NECESSITIES
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    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
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    • A61K36/9066—Curcuma, e.g. common turmeric, East Indian arrowroot or mango ginger
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/88—Liliopsida (monocotyledons)
    • A61K36/906—Zingiberaceae (Ginger family)
    • A61K36/9068—Zingiber, e.g. garden ginger
    • 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
    • A61P31/10—Antimycotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to metallo- ⁇ -lactamase inhibitors and their uses.
  • Non-Patent Document 1 carbapenem antibiotics, which have traditionally been used as a last resort treatment for multidrug-resistant bacterial infections, are degraded by metallo- ⁇ -lactamases (Non-Patent Document 1), and there has been a problem in that they cannot treat infections caused by multidrug-resistant gram-negative bacteria.
  • the objective of the present invention is therefore to discover substances that inhibit the resistance mechanisms of multidrug-resistant Gram-negative bacteria and that inhibit the effectiveness of existing antibacterial drugs.
  • Patent Document 1 anti-aging effects
  • Patent Document 2 spontaneous cancer prevention effects
  • Patent Document 3 immune checkpoint inhibitory effects
  • Patent Document 4 QOL improvement effects
  • the present invention provides the following (a) to (g): (a) Aspergillus oryzae fermentation products of beans and grains consisting of barley, black soybeans, red rice, black rice, red beans, pearl barley, barnyard millet, foxtail millet, and millet; (b) yeast and/or lactic acid bacteria fermentation products of fruits consisting of mandarin oranges, grapes, apples, wild grapes, peaches, persimmons, papayas, pears, watermelons, plums, figs, quince, pumpkins, kumquats, yuzu, loquats, apricots, jujubes, chestnuts, silver vine, and plums; (c) purple sweet potatoes, Jerusalem artichokes, carrots, onions, sweet potatoes, taro, wild yams, radishes, red turnips, burdock, lotus root, yacon, lily root, water chestnut, ginger, garlic, and turmeric.
  • yeast and/or lactic acid bacteria fermentation products of flower and leaf vegetables such as cabbage, shiso, mulberry leaves, dokudami, mugwort, kumazasa, and dandelion
  • yeast and/or lactic acid bacteria fermentation products of seaweed such as kombu, wakame, and mozuku
  • yeast and/or lactic acid bacteria fermentation products of seeds such as black sesame, walnut, and ginkgo
  • a plant fermentation product that is a mixture of yeast and/or lactic acid bacteria fermentation products of mushrooms such as maitake and shiitake.
  • the present invention also relates to a food product for treating multidrug-resistant gram-negative bacteria that contains the above-mentioned metallo- ⁇ -lactamase inhibitor.
  • the present invention is a composition for use against multidrug-resistant Gram-negative bacteria that contains the above-mentioned metallo- ⁇ -lactamase inhibitor and an antibacterial agent.
  • the present invention relates to a method for controlling multidrug-resistant gram-negative bacteria, which comprises administering an antibacterial agent and the above-mentioned metallo- ⁇ -lactamase inhibitor to the multidrug-resistant gram-negative bacteria.
  • the present invention relates to a method for treating a disease associated with multidrug-resistant gram-negative bacteria, which comprises administering an antibacterial agent and the above-mentioned metallo- ⁇ -lactamase inhibitor to an animal suffering from a disease associated with multidrug-resistant gram-negative bacteria.
  • the metallo- ⁇ -lactamase inhibitor of the present invention uses as its active ingredient a specific fermented plant product that has been widely consumed, and can therefore be safely used in the control and treatment of multidrug-resistant gram-negative bacteria, as well as in foods for anti-multidrug-resistant gram-negative bacteria, etc.
  • the metallo- ⁇ -lactamase inhibitors of the present invention are suitable for treating diseases associated with multidrug-resistant gram-negative bacteria, such as infectious diseases.
  • FIG. 1 is a diagram showing the measurement of minimum inhibitory concentration in Example 1 (1).
  • FIG. 2 shows the results of the combination test of Example 1 (2) (in the figure, the upper left is a plate with 0 plant fermentation product, the upper right is a plate with 1/10 plant fermentation product, the lower left is information showing the type of antibiotic and its concentration, and the lower right is a plate with 1/16 plant fermentation product (gold seal)).
  • FIG. 3 is a diagram showing the results of the checkerboard test in Example 1(3).
  • FIG. 4 shows the results of the nitrocefin test.
  • the metallo- ⁇ -lactamase inhibitor of the present invention contains the following plant fermentation product as an active ingredient.
  • This plant fermentation product is a mixture of the following plant fermentation products (a) to (g).
  • a fermented product obtained by applying koji mold to beans and grains including barley, black soybeans, red rice, black rice, adzuki beans, barley, barnyard millet, foxtail millet, and millet.
  • Fermented products obtained by applying yeast and/or lactic acid bacteria to fruits such as mandarin oranges, grapes, apples, wild grapes, peaches, persimmons, papayas, pears, watermelons, plums, figs, quince, pumpkins, kumquats, yuzu, loquats, apricots, jujubes, chestnuts, silver vines, and plums, preferably fermented products obtained by applying yeast to the fruits.
  • a fermented product obtained by applying yeast and/or lactic acid bacteria to flower and leaf vegetables consisting of cabbage, shiso, mulberry leaves, dokudami, mugwort, kumazasa, and dandelion, preferably a fermented product obtained by applying lactic acid bacteria to the flower and leaf vegetables.
  • a fermented product obtained by applying yeast and/or lactic acid bacteria to seeds consisting of black sesame, walnuts and ginkgo nuts, preferably a fermented product obtained by applying yeast to the seeds.
  • a fermented product obtained by applying yeast and/or lactic acid bacteria to mushrooms consisting of Maitake and Shiitake, preferably a fermented product obtained by applying lactic acid bacteria to the mushrooms.
  • the metallo- ⁇ -lactamase inhibitor of the present invention may be a mixture of the fermented plant products (a) to (g) as an active ingredient, but by further fermenting it in multiple stages, the taste and formulation properties can be improved.
  • yeast examples include yeasts belonging to the genera Saccharomyces and Zygosaccharomyces, among which Saccharomyces cerevisiae (S. cervisiae), Zygosaccharomyces rouxii, Saccharomyces exiguus, etc. are preferably used.
  • lactic acid bacteria examples include lactic acid bacteria belonging to the genera Pediococcus, Leuconostoc, Lactobacillus, Lactococcus, etc., among which Pediococcus acidilacti (P. acidilacti), Lactobacillus brevis, Leuconostoc mesenteroides, Lactobacillus ketosporum ...
  • Lactobacillus plantarum Lactococcus lactis, Lactobacillus sakei, Pediococcus pentosaceus, Lactobacillus casei, Lactobacillus reuteri, and Lactobacillus curvatus are preferably used, and one or more of these may be used.
  • koji mold include Aspergillus oryzae, Aspergillus niger, and Aspergillus kawachii, and one or more of these may be used. These yeasts, lactic acid bacteria, and koji molds may be commercially available or obtained from depositories, etc., and may be used.
  • Beans, grains, fruits, and other plants to be fermented may be used as is, or may be pretreated by crushing, drying, etc. as necessary. Water may also be added to dilute the product as necessary.
  • the fermented products (a) to (g) above are obtained by inoculating the plant material with lactic acid bacteria, yeast or koji mold and culturing it. Cultivation can be carried out by a conventional method, for example, by adding about 0.001 to 1% by mass of lactic acid bacteria, yeast or koji mold to a mixture of one or more types of plants, and fermenting it at 20 to 50°C for about 70 to 140 hours.
  • the fermented products (a) to (g) thus obtained can be mixed and used as an active ingredient as is, but it is preferable to further culture the mixture at 20 to 40°C for about 200 to 300 hours if necessary. It is also preferable to post-ferment (maturity) this mixture. Post-fermentation may be performed using acetic acid bacteria if necessary. For example, the above-mentioned yeast may be applied to one or more of the plants included in (a) to (g) above, and an acetic acid fermentation product obtained by applying acetic acid bacteria such as Acetobacter aceti (A. acetate) may be added to the mixture. Post-fermentation may be performed at 25 to 35°C for 70 hours to about one year. The post-fermentation can be performed through a maturation process to improve the taste and formulation properties, and also to increase antioxidant activity.
  • acetic acid bacteria such as Acetobacter aceti (A. acetate)
  • a suitable example of a method for producing the above-mentioned plant fermentation products is the multi-stage complex fermentation method.
  • a complex lactic acid bacteria fermentation product made primarily from fruits, vegetables, and seaweed is mixed with a yeast fermentation product made primarily from vegetables, root vegetables, seeds, mushrooms, and fruits, to which is added a koji mold fermentation product made primarily from grains and beans, and then an acetic acid fermentation product is added and mixed, after which the mixture is filtered and concentrated, and then post-fermented for about a year.
  • a complex lactic acid bacteria fermentation product made primarily from fruits, vegetables, and seaweed
  • a yeast fermentation product made primarily from vegetables, root vegetables, seeds, mushrooms, and fruits
  • a koji mold fermentation product made primarily from grains and beans
  • an acetic acid fermentation product is added and mixed, after which the mixture is filtered and concentrated, and then post-fermented for about a year.
  • each fermentation product is further assimilated and converted by different fungi, which is thought to improve the flavor and
  • the fermented plant product as an active ingredient used in the metallo- ⁇ -lactamase inhibitor of the present invention has the following properties (1) to (4).
  • Flavor It has the sweetness derived from the koji in addition to the sweetness and organic acids derived from the fruits and vegetables. Although it contains polyphenols derived from the raw materials, it has little bitterness.
  • Solubility in Water Easily soluble in water.
  • Stability It is stable against heat and acid, and the paste can be stored at room temperature for one year without spoilage or change in taste.
  • Safety The vegetables, fruits, herbs, etc. used as ingredients are commonly consumed, and the yeast, lactic acid bacteria, and koji mold used for fermentation are all species derived from food brewing and pickling, and are therefore widely consumed.
  • the fermented plant product used in the present invention has the following properties (A) to (D).
  • the above-mentioned plant fermentation product has a metallo- ⁇ -lactamase inhibitory effect, and therefore can be used as a metallo- ⁇ -lactamase inhibitor by using it as an active ingredient.
  • metallo- ⁇ -lactamase that can be inhibited by the plant fermentation product, and examples include NDM-type metallo- ⁇ -lactamase and IMP-type metallo- ⁇ -lactamase, but preferably NDM-type metallo- ⁇ -lactamase, which is of concern for its global geographical spread and its spread between different bacterial species to Enterobacteriaceae bacteria, including various pathogenic bacteria.
  • the plant fermentation products described above have an inhibitory effect on metallo- ⁇ -lactamase, and therefore can be used as metallo- ⁇ -lactamase inhibitors. Whether or not a plant fermentation product has an inhibitory effect on metallo- ⁇ -lactamase can be confirmed by the tests described in the Examples. Furthermore, the metallo- ⁇ -lactamase inhibitory effect of the plant fermentation product described above shows a synergistic effect with several ⁇ g of an antibiotic when the protein amount is approximately 20 ⁇ g or more, preferably 30 to 60 ⁇ g.
  • the metallo- ⁇ -lactamase inhibitor of the present invention may be prepared by using the above-mentioned plant fermentation product as it is, or by adding pharmacologically acceptable carriers, excipients, water activity regulators, etc. according to known pharmaceutical manufacturing methods.
  • the plant fermentation product may be concentrated to adjust the concentration as necessary, or may be powdered by spraying or freeze-drying.
  • carriers and excipients used in formulation include lactose, glucose, sucrose, starch, and sugar mixtures.
  • final forms include solutions, pastes, soft capsules, chewable tablets, capsules, powders, granules, syrups, oral liquids, sprays, ointments, creams, external liquids, eye drops, nasal drops, suppositories, and patches.
  • dosage and method of use for example, 0.1 g or more, preferably 0.1 to 12 g, and more preferably 0.6 to 10 g (in terms of solid content) of the plant fermentation product as the active ingredient may be orally taken by an adult per day.
  • Examples of commercially available products in which such plant fermentation products have been formulated and made into food products include Tensei Koso Kinjirushi, Tensei Koso Capsules, and Amou Koso (all manufactured by Nihon Shizen Hakkou Co., Ltd.).
  • the metallo- ⁇ -lactamase inhibitor of the present invention can be administered together with an antibacterial agent to animals with a multidrug-resistant gram-negative bacteria-associated disease, preferably animals other than humans with a multidrug-resistant gram-negative bacteria-associated disease, to treat the multidrug-resistant gram-negative bacteria-associated disease.
  • a multidrug-resistant gram-negative bacteria-associated disease preferably animals other than humans with a multidrug-resistant gram-negative bacteria-associated disease
  • multidrug-resistant gram-negative bacteria-associated disease preferably animals other than humans with a multidrug-resistant gram-negative bacteria-associated disease
  • infections include pneumonia and sepsis.
  • examples of the antibacterial agent include, but are not limited to, penicillin-based antibacterial agents such as benzylpenicillin potassium (PCG), oxacillin sodium (MPIPC), ampicillin sodium (ABPC), amoxicillin (AMPC), piperacillin sodium (PIPC), and sultamicillin tosylate (SBTPC); cephalothin sodium (CET), cefazolin sodium (CEZ), cefotiam hydrochloride (CTM), cefoperazone sodium (CPZ), cefotaxime sodium (CTX), ceftizoxime sodium (CZX), cefmenoxime hydrochloride (CMX), ceftazidime (CAZ), ceftriaxone sodium (CTRX), and cefpirimidazole sulfate (CTRX).
  • PCG benzylpenicillin potassium
  • MPIPC oxacillin sodium
  • ABPC ampicillin sodium
  • AMPC amoxicillin
  • PIPC piperacillin sodium
  • cephem antibiotics such as cephalosporin (CPR), cefepime hydrochloride (CFPM), cefozopran hydrochloride (CZOP), cephalexin (CEX), cefaclor (CCL), cefroxadine (CXD), cefixime (CFIX), ceftibuten (CETB), cefdinir (CFDN), cefuroxime sodium (CXM), cefpodoxime sodium (CPDX), cefteram hydrochloride (CFTM), cefcapene sodium (CFPN), and cefditoren sodium (CDTR); and carbapenem antibiotics such as imipenem (IPM), meropenem trihydrate (MEPM), biapenem (BIPM), doripenem hydrate (DRPM), and tebipenem hydrate (TBPM).
  • CPR cephalosporin
  • CFPM cefepime hydrochloride
  • CZOP cefozopran hydrochloride
  • CEX cef
  • the method of administering the metallo- ⁇ -lactamase inhibitor of the present invention to animals with multidrug-resistant gram-negative bacteria-associated diseases is not particularly limited, and may be either topical or oral administration.
  • the metallo- ⁇ -lactamase inhibitor of the present invention inhibits the resistance mechanism of multidrug-resistant gram-negative bacteria, allowing existing antibacterial drugs to be effective. Therefore, by administering an antibacterial drug and the metallo- ⁇ -lactamase inhibitor of the present invention to multidrug-resistant gram-negative bacteria, the multidrug-resistant gram-negative bacteria can be controlled.
  • multidrug-resistant gram-negative bacteria refers to gram-negative bacteria that are resistant to the above-mentioned antibacterial drugs and whose growth is not inhibited by the antibacterial drugs.
  • a composition for use against multidrug-resistant gram-negative bacteria containing the metallo- ⁇ -lactamase inhibitor of the present invention and the above-mentioned antibacterial agent may be used.
  • the content of the antibacterial agent in this composition is not particularly limited, and may be any amount at which the antibacterial agent is normally effective.
  • the anti-multidrug resistant Gram-negative bacteria composition of the present invention described above can be formulated in the same manner as the metallo- ⁇ -lactamase inhibitor of the present invention.
  • the final form may be a solution, paste, soft capsule, chewable tablet, capsule, powder, granule, syrup, oral liquid, spray, ointment, cream, topical liquid, eye drops, nasal drops, suppositories, patches, etc., in the same manner as the metallo- ⁇ -lactamase inhibitor of the present invention.
  • the metallo- ⁇ -lactamase inhibitor of the present invention is also a food ingredient that has a long history of use in food, and can therefore be used as a food for anti-multidrug-resistant gram-negative bacteria.
  • This food can be made by simply using the plant fermentation product, which is the active ingredient of the metallo- ⁇ -lactamase inhibitor of the present invention, as part of a conventional food ingredient or seasoning.
  • foods include seasonings such as miso, breads such as white bread, confectioneries such as rice crackers, cookies, chocolate, candy, buns, and cakes, dairy products such as yogurt and cheese, pickles such as takuan, noodles such as ramen, soba, and udon, soups such as corn potage and wakame seaweed soup, soft drinks, health drinks, carbonated drinks, and fruit juice drinks.
  • the above raw materials (c), (d) and (g) (730 g) were inoculated with 0.2% by mass of a culture solution prepared so that lactic acid bacteria (P. acidilacti, L. brevis, L. mesenteroides, L. plantarum, L. lactis, L. sakei, L. casei) had a bacterial concentration of about 1.0 x 105 cfu/g, and cultured for 50 hours at 30°C.
  • the above raw materials (b), (e) and (f) (900 kg) were inoculated with 0.4% by mass of a culture solution prepared so that yeasts (5 species of S. cervisiae, 2 species of Z.
  • rouxii had a bacterial concentration of about 1.0 x 105 cfu/g, and cultured for 50 hours at 30°C.
  • Bean and cereal raw materials 1000 kg were inoculated with 0.1% by mass of koji mold (yellow koji mold, black koji mold, white koji mold) and cultured for 70 hours at 35° C. Then, the cultures were mixed and cultured for 200 hours at 30° C. The fermented moromi was subjected to solid-liquid separation, and the obtained filtrate was concentrated into a paste, which was dispensed into containers and further fermented (aged) for one year to obtain a plant fermentation product.
  • the plant fermentation product obtained in Production Example 1 had the following properties.
  • This plant fermentation product is the same as Tensei Koso Kinjirushi (manufactured by Nihon Shizen Hakko Co., Ltd.), and was used in the following examples.
  • Example 1 Properties of the fermented plant product prepared in Production Example 1: (1) Measurement of minimum inhibitory concentration The plant fermentation product prepared in Production Example 1 was weighed, and twice the amount of sterilized water was added, and the mixture was left to soak overnight to elute the components. After centrifugation, the supernatant was filtered through a 0.22 ⁇ m filter to prepare a sample. Using this sample, the MIC against multidrug-resistant Gram-negative bacteria was examined.
  • Combination test A combination test was performed using a drug susceptibility test plate (Dry Plate Eiken: Eiken Chemical Co., Ltd.) on which a concentration gradient series of various antibacterial drugs was immobilized and multidrug-resistant gram-negative bacteria. The results are shown in Figure 2. Each plate was added with 0, 1/10 or 1/16 of the plant fermentation product (sample), and a fixed amount of multidrug-resistant gram-negative bacteria.
  • Nitrocefin test To examine the activity of metallo- ⁇ -lactamase, a nitrocefin test was performed according to a standard method (Ishii Yoshikazu et al., "Study on the establishment of a method for measuring ⁇ -lactamase activity in sputum," Journal of the Japanese Society of Chemotherapy, Vol. 47, No. 10, p. 619-622 (1999)). In the presence of plant fermentation products (fermentation liquid in the figure), the red color development due to the decomposition of nitrocefin was suppressed compared to the positive control, indicating that existing antibacterial drugs such as carbapenems were effective due to the reduced activity of metallo- ⁇ -lactamase ( Figure 4). Mercaptoacetic acid is a known metallo- ⁇ -lactamase inhibitor in vitro.
  • Example 2 Preparation of a composition for use against multidrug-resistant Gram-negative bacteria: 10 g of the plant fermentation product prepared in Example 1 was mixed with 0.5 g of an antibiotic (meropenem), diluted with water, and the taste was adjusted to prepare a liquid composition against multidrug-resistant gram-negative bacteria.
  • an antibiotic meropenem
  • Example 3 Preparation of a composition for use against multidrug-resistant Gram-negative bacteria: A paste-like composition for anti-multidrug-resistant gram-negative bacteria was prepared by mixing 10 g of the plant fermentation product prepared in Example 1 with 0.5 g of an antibacterial agent (meropenem).
  • Example 4 Food for anti-multidrug resistant gram-negative bacteria (miso-like food): The plant fermented product produced in Production Example 1 was mixed with miso, and the taste was adjusted with seasonings to produce a food for multidrug-resistant gram-negative bacteria (miso-like food).
  • Example 5 Foods (drinks) for anti-multidrug resistant gram-negative bacteria: The plant fermentation product produced in Production Example 1 was dissolved in water, and then mixed with fructose glucose liquid and fruit juice, and the taste was adjusted to produce a food (drink) for use against multidrug-resistant gram-negative bacteria.
  • Example 6 Food for anti-multidrug resistant gram-negative bacteria (soft capsule): The plant fermentation product produced in Production Example 1 was mixed with vegetable oil and lecithin and filled into soft capsules in a conventional manner to produce a food product (soft capsule) against multidrug-resistant gram-negative bacteria.
  • Example 7 Food for anti-multidrug resistant gram-negative bacteria (chewable tablets): The plant fermentation product produced in Production Example 1 was mixed with crystalline cellulose and sucrose and tableted in a conventional manner to produce an anti-multidrug resistant Gram-negative bacteria food (chewable tablet) for use in improving QOL.
  • Example 8 Food for anti-multidrug resistant gram-negative bacteria (soft capsule): The plant fermentation product (daily amount) produced in Production Example 1 was mixed with vegetable oil, lecithin and 900 mg of anserine and filled into soft capsules in a conventional manner to produce a food product (soft capsule) against multidrug-resistant gram-negative bacteria.
  • the metallo- ⁇ -lactamase inhibitor of the present invention inhibits the resistance mechanism of multidrug-resistant gram-negative bacteria, enabling antibacterial drugs to be effective, and can therefore be used to treat diseases associated with multidrug-resistant gram-negative bacteria. that's all

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Abstract

The purpose of the present invention is to search for a substance that inhibits the resistance mechanism of multidrug-resistant gram-negative bacteria and that enables existing antimicrobial agents to exhibit an effect. This metallo-β-lactamase inhibitor comprises, as an active ingredient, a plant fermented product that is a mixture of (a) an Aspergillus-fermented product of beans and grains including barley, black soybean, red rice, black rice, red bean, adlay, barnyard millet, foxtail millet, and proso millet, (b) a yeast and/or lactic acid bacterium-fermented product of fruits including Japanese mandarin, grape, apple, fox grape, peach, persimmon, and the like, (c) a yeast and/or lactic acid bacterium-fermented product of root vegetables and potatoes including purple yam, Jerusalem artichoke, carrot, onion, sweet potato, taro, and the like, (d) a yeast and/or lactic acid bacterium-fermented product of flowers and leaf vegetables including cabbage, shiso, mulberry leaf, Houttuynia cordata, Artemisia princeps, Sasa veitchii, and dandelion, (e) a yeast and/or lactic acid bacterium-fermented product of seaweed including kelp, wakame, and Nemacystus decipiens, (f) a yeast and/or lactic acid bacterium-fermented product of seeds including black sesame, walnut, and ginkgo biloba seeds, and (g) a yeast and/or lactic acid bacterium-fermented product of mushrooms including Grifola frondosa and Lentinula edodes.

Description

メタロ－β－ラクタマーゼ阻害剤およびその利用Metallo-beta-lactamase inhibitors and uses thereof

　本発明は、メタロ－β－ラクタマーゼ阻害剤およびその利用に関する。 The present invention relates to metallo-β-lactamase inhibitors and their uses.

　多剤耐性グラム陰性菌による感染症は既存の抗菌薬がほとんど効かず、世界規模での深刻な問題となっている。 Infections caused by multidrug-resistant gram-negative bacteria are largely ineffective against existing antibiotics and have become a serious problem on a global scale.

　特に、多剤耐性菌感染症の切り札的治療薬として従来使用されてきたカルバペネム系抗菌薬はメタロ－β－ラクタマーゼにより分解されてしまい（非特許文献１）、多剤耐性グラム陰性菌による感染症を治療できないという問題があった。 In particular, carbapenem antibiotics, which have traditionally been used as a last resort treatment for multidrug-resistant bacterial infections, are degraded by metallo-β-lactamases (Non-Patent Document 1), and there has been a problem in that they cannot treat infections caused by multidrug-resistant gram-negative bacteria.

国際公開パンフレットＷＯ２０１６／０９３１０４International Publication Pamphlet WO2016/093104 国際公開パンフレットＷＯ２０１９／００９４３７International Publication Pamphlet WO2019/009437 国際公開パンフレットＷＯ２０１９／００９４３８International Publication Pamphlet WO2019/009438 国際公開パンフレットＷＯ２０２２／００３７４９International Publication Pamphlet WO2022/003749

M Tilahun et al. Emerging Carbapenem-Resistant Enterobacteriaceae Infection, Its Epidemiology and Novel Treatment Options: A ReviewInfectin and Drug Resistance 2021 Oct 21;14:4363-4374.M Tilahun et al. Emerging Carbapenem-Resistant Enterobacteriaceae Infection, Its Epidemiology and Novel Treatment Options: A ReviewInfectin and Drug Resistance 2021 Oct 21;14:4363-4374.

　従って、本発明は、多剤耐性グラム陰性菌の耐性機構を阻害し、既存の抗菌薬が効果を発揮する物質を探索することを課題とした。 The objective of the present invention is therefore to discover substances that inhibit the resistance mechanisms of multidrug-resistant Gram-negative bacteria and that inhibit the effectiveness of existing antibacterial drugs.

　本発明者らは、上記課題を解決するために鋭意研究したところ、これまで本発明者らが開発してきた、老化抑制作用（特許文献１）、自然発がん予防作用（特許文献２）、免疫チェックポイント阻害作用（特許文献３）、ＱＯＬ改善作用（特許文献４）を明らかにしてきた植物発酵物が、多剤耐性グラム陰性菌の耐性機構を阻害し、既存の抗菌薬が効果を発揮できるようになることを見出し、本発明を完成させた。 The inventors conducted intensive research to solve the above problems, and discovered that the plant fermentation products they have developed to date, which have been shown to have anti-aging effects (Patent Document 1), spontaneous cancer prevention effects (Patent Document 2), immune checkpoint inhibitory effects (Patent Document 3), and QOL improvement effects (Patent Document 4), inhibit the resistance mechanisms of multidrug-resistant Gram-negative bacteria, allowing existing antibacterial drugs to be effective, thus completing the present invention.

　すなわち、本発明は、次の（ａ）～（ｇ）
（ａ）大麦、黒大豆、赤米、黒米、小豆、はと麦、ヒエ、アワおよびキビからなる豆・穀物類の麹菌発酵物
（ｂ）ミカン、ブドウ、リンゴ、ヤマブドウ、モモ、カキ、パパイヤ、ナシ、スイカ、ウメ、イチジク、カリン、カボチャ、キンカン、ユズ、ビワ、アンズ、ナツメ、クリ、マタタビおよびスモモからなる果実類の酵母および／又は乳酸菌発酵物
（ｃ）紫イモ、菊芋、ニンジン、タマネギ、サツマイモ、里芋、自然薯、大根、赤カブ、ゴボウ、レンコン、ヤーコン、ユリ根、クワイ、しょうが、にんにくおよびウコンからなる根菜類・イモ類の酵母および／又は乳酸菌発酵物
（ｄ）キャベツ、紫蘇、桑葉、どくだみ、ヨモギ、クマザサおよびタンポポからなる花・葉菜類の酵母および／又は乳酸菌発酵物
（ｅ）コンブ、ワカメおよびモズクからなる海藻類の酵母および／又は乳酸菌発酵物
（ｆ）黒ゴマ、クルミおよびギンナンからなる種子類の酵母および／又は乳酸菌発酵物
（ｇ）マイタケおよびシイタケからなるキノコ類の酵母および／又は乳酸菌発酵物
の混合物である植物発酵物を有効成分として含有するメタロ－β－ラクタマーゼ阻害剤である。 That is, the present invention provides the following (a) to (g):
(a) Aspergillus oryzae fermentation products of beans and grains consisting of barley, black soybeans, red rice, black rice, red beans, pearl barley, barnyard millet, foxtail millet, and millet; (b) yeast and/or lactic acid bacteria fermentation products of fruits consisting of mandarin oranges, grapes, apples, wild grapes, peaches, persimmons, papayas, pears, watermelons, plums, figs, quince, pumpkins, kumquats, yuzu, loquats, apricots, jujubes, chestnuts, silver vine, and plums; (c) purple sweet potatoes, Jerusalem artichokes, carrots, onions, sweet potatoes, taro, wild yams, radishes, red turnips, burdock, lotus root, yacon, lily root, water chestnut, ginger, garlic, and turmeric. (d) yeast and/or lactic acid bacteria fermentation products of flower and leaf vegetables such as cabbage, shiso, mulberry leaves, dokudami, mugwort, kumazasa, and dandelion; (e) yeast and/or lactic acid bacteria fermentation products of seaweed such as kombu, wakame, and mozuku; (f) yeast and/or lactic acid bacteria fermentation products of seeds such as black sesame, walnut, and ginkgo; and (g) a plant fermentation product that is a mixture of yeast and/or lactic acid bacteria fermentation products of mushrooms such as maitake and shiitake.

　また、本発明は、上記メタロ－β－ラクタマーゼ阻害剤を含有する抗多剤耐性グラム陰性菌用食品である。 The present invention also relates to a food product for treating multidrug-resistant gram-negative bacteria that contains the above-mentioned metallo-β-lactamase inhibitor.

　更に、本発明は、上記メタロ－β－ラクタマーゼ阻害剤と、抗菌薬とを含有する抗多剤耐性グラム陰性菌用組成物である。 Furthermore, the present invention is a composition for use against multidrug-resistant Gram-negative bacteria that contains the above-mentioned metallo-β-lactamase inhibitor and an antibacterial agent.

　また更に、本発明は、多剤耐性グラム陰性菌に、抗菌薬と、上記メタロ－β－ラクタマーゼ阻害剤を投与することを特徴とする多剤耐性グラム陰性菌の制御方法である。 Furthermore, the present invention relates to a method for controlling multidrug-resistant gram-negative bacteria, which comprises administering an antibacterial agent and the above-mentioned metallo-β-lactamase inhibitor to the multidrug-resistant gram-negative bacteria.

　更にまた、本発明は、多剤耐性グラム陰性菌関連疾患の動物に、抗菌薬と、上記メタロ－β－ラクタマーゼ阻害剤を投与することを特徴とする多剤耐性グラム陰性菌関連疾患の治療方法である。 Furthermore, the present invention relates to a method for treating a disease associated with multidrug-resistant gram-negative bacteria, which comprises administering an antibacterial agent and the above-mentioned metallo-β-lactamase inhibitor to an animal suffering from a disease associated with multidrug-resistant gram-negative bacteria.

　本発明のメタロ－β－ラクタマーゼ阻害剤は、これまでも食経験の豊かな特定の植物発酵物を有効成分とするため、安全に多剤耐性グラム陰性菌の制御や治療等の処理、抗多剤耐性グラム陰性菌用食品等の用途に使用することができる。 The metallo-β-lactamase inhibitor of the present invention uses as its active ingredient a specific fermented plant product that has been widely consumed, and can therefore be safely used in the control and treatment of multidrug-resistant gram-negative bacteria, as well as in foods for anti-multidrug-resistant gram-negative bacteria, etc.

　特に、本発明のメタロ－β－ラクタマーゼ阻害剤は、感染症等の多剤耐性グラム陰性菌関連疾患の治療に好適である。 In particular, the metallo-β-lactamase inhibitors of the present invention are suitable for treating diseases associated with multidrug-resistant gram-negative bacteria, such as infectious diseases.

図１は実施例１の（１）最小発育阻止濃度の測定を示す図である。FIG. 1 is a diagram showing the measurement of minimum inhibitory concentration in Example 1 (1). 図２は実施例１の（２）コンビネーション試験の結果を示す図である（図中、左上は植物発酵物が０のプレート、右上が植物発酵物が１／１０のプレート、左下が抗菌薬の種類とその濃度を示す情報、右下が植物発酵物（金印）１／１６のプレートである）。FIG. 2 shows the results of the combination test of Example 1 (2) (in the figure, the upper left is a plate with 0 plant fermentation product, the upper right is a plate with 1/10 plant fermentation product, the lower left is information showing the type of antibiotic and its concentration, and the lower right is a plate with 1/16 plant fermentation product (gold seal)). 図３は実施例１の（３）チェッカーボード試験の結果を示す図である。FIG. 3 is a diagram showing the results of the checkerboard test in Example 1(3). 図４はニトロセフィン試験の結果を示す図である。FIG. 4 shows the results of the nitrocefin test.

　本発明のメタロ－β－ラクタマーゼ阻害剤は、下記の植物発酵物を有効成分として含有するものである。この植物発酵物は、以下の（ａ）～（ｇ）の植物発酵物の混合物である。 The metallo-β-lactamase inhibitor of the present invention contains the following plant fermentation product as an active ingredient. This plant fermentation product is a mixture of the following plant fermentation products (a) to (g).

　（ａ）大麦、黒大豆、赤米、黒米、小豆、はと麦、ヒエ、アワおよびキビからなる豆・穀類に麹菌を作用させることにより得られる発酵物 (a) A fermented product obtained by applying koji mold to beans and grains, including barley, black soybeans, red rice, black rice, adzuki beans, barley, barnyard millet, foxtail millet, and millet.

　（ｂ）ミカン、ブドウ、リンゴ、ヤマブドウ、モモ、カキ、パパイヤ、ナシ、スイカ、ウメ、イチジク、カリン、カボチャ、キンカン、ユズ、ビワ、アンズ、ナツメ、クリ、マタタビおよびスモモからなる果実類に酵母および／又は乳酸菌を作用させることにより得られる発酵物、好ましくは前記果実類に酵母を作用させることにより得られる発酵物 (b) Fermented products obtained by applying yeast and/or lactic acid bacteria to fruits such as mandarin oranges, grapes, apples, wild grapes, peaches, persimmons, papayas, pears, watermelons, plums, figs, quince, pumpkins, kumquats, yuzu, loquats, apricots, jujubes, chestnuts, silver vines, and plums, preferably fermented products obtained by applying yeast to the fruits.

　（ｃ）紫イモ、菊芋、ニンジン、タマネギ、サツマイモ、里芋、自然薯、大根、赤カブ、ゴボウ、レンコン、ヤーコン、ユリ根、クワイ、しょうが、にんにくおよびウコンからなる根菜類・イモ類に酵母および／又は乳酸菌を作用させることにより得られる発酵物、好ましくは前記根菜類・イモ類に乳酸菌を作用させることにより得られる発酵物 (c) Fermented products obtained by applying yeast and/or lactic acid bacteria to root vegetables and tubers consisting of purple sweet potato, Jerusalem artichoke, carrot, onion, sweet potato, taro, wild yam, radish, red turnip, burdock, lotus root, yacon, lily root, arrowhead, ginger, garlic and turmeric, preferably fermented products obtained by applying lactic acid bacteria to the above root vegetables and tubers.

　（ｄ）キャベツ、紫蘇、桑葉、どくだみ、ヨモギ、クマザサおよびタンポポからなる花・葉菜類に酵母および／又は乳酸菌を作用させることにより得られる発酵物、好ましくは前記花・葉菜類に乳酸菌を作用させることにより得られる発酵物 (d) A fermented product obtained by applying yeast and/or lactic acid bacteria to flower and leaf vegetables consisting of cabbage, shiso, mulberry leaves, dokudami, mugwort, kumazasa, and dandelion, preferably a fermented product obtained by applying lactic acid bacteria to the flower and leaf vegetables.

　（ｅ）コンブ、ワカメおよびモズクからなる海藻類に酵母および／又は乳酸菌を作用させることにより得られる発酵物、好ましくは前記海藻類に酵母を作用させることにより得られる発酵物 (e) A fermented product obtained by applying yeast and/or lactic acid bacteria to seaweeds consisting of kombu, wakame and mozuku, preferably a fermented product obtained by applying yeast to the seaweeds.

　（ｆ）黒ゴマ、クルミおよびギンナンからなる種子類に酵母および／又は乳酸菌を作用させることにより得られる発酵物、好ましくは前記種子類に酵母を作用させることにより得られる発酵物 (f) A fermented product obtained by applying yeast and/or lactic acid bacteria to seeds consisting of black sesame, walnuts and ginkgo nuts, preferably a fermented product obtained by applying yeast to the seeds.

　（ｇ）マイタケおよびシイタケからなるキノコ類に酵母および／又は乳酸菌を作用させることにより得られる発酵物、好ましくは前記キノコ類に乳酸菌を作用させることにより得られる発酵物 (g) A fermented product obtained by applying yeast and/or lactic acid bacteria to mushrooms consisting of Maitake and Shiitake, preferably a fermented product obtained by applying lactic acid bacteria to the mushrooms.

　本発明のメタロ－β－ラクタマーゼ阻害剤は、上記（ａ）～（ｇ）の発酵物を混合した植物発酵物をそのまま有効成分としてもよいが、さらに多段階発酵させることにより、呈味性や製剤性を向上させることができる。 The metallo-β-lactamase inhibitor of the present invention may be a mixture of the fermented plant products (a) to (g) as an active ingredient, but by further fermenting it in multiple stages, the taste and formulation properties can be improved.

　酵母としては、サッカロマイセス属、ジゴサッカロマイセス属等に属する酵母が挙げられ、中でもサッカロマイセス・セレビシエ（S. cervisiae）、ジゴサッカロマイセス・ロキシー（Z. rouxii）、サッカロマイセス・エキシグス（S.exiguus）等が好ましく用いられる。乳酸菌としては、例えば、ぺディオコッカス（Pediococcus）属、ロイコノストック（Leuconostoc）属、ラクトバチルス（Lactobacillus）属、ラクトコッカス（Lactococcus）属等に属する乳酸菌が挙げられ、中でも、ぺディオコッカス・アシディラクティ（P.acidilacti）、ラクトバチルス・ブレビス（L. brevis）、ロイコノストック・メセンテロイデス（L. mesenteroides）、ラクトバチルス・プランタラム（L. plantarum）、ラクトコッカス・ラクチス（L. lactis）、ラクトバチルス・サケイ（L. sakei）、ペディオコッカス・ペントサセウス（P. pentosaceus）、ラクトバチルス・カゼイ（L. casei）、ラクトバチルス・ロイテリ（L.reuteri）およびラクトバチルス・クルバタス（L. curvatus）等が好ましく用いられ、これらの１種または２種以上を使用することができる。麹菌としては、アスペルギルス・オリゼー（Aspergillus oryzae）、アスペルギルス・ニガー（Aspergillus niger）、アスペルギルス・カワチ（Aspergillus kawachii）等が例示でき、これらの１種又は２種以上を使用できる。これらの酵母、乳酸菌、麹菌は市販されているものや、寄託機関等から入手したもの等を使用することができる。 Examples of yeast include yeasts belonging to the genera Saccharomyces and Zygosaccharomyces, among which Saccharomyces cerevisiae (S. cervisiae), Zygosaccharomyces rouxii, Saccharomyces exiguus, etc. are preferably used. Examples of lactic acid bacteria include lactic acid bacteria belonging to the genera Pediococcus, Leuconostoc, Lactobacillus, Lactococcus, etc., among which Pediococcus acidilacti (P. acidilacti), Lactobacillus brevis, Leuconostoc mesenteroides, Lactobacillus ketosporum ... Lactobacillus plantarum, Lactococcus lactis, Lactobacillus sakei, Pediococcus pentosaceus, Lactobacillus casei, Lactobacillus reuteri, and Lactobacillus curvatus are preferably used, and one or more of these may be used. Examples of koji mold include Aspergillus oryzae, Aspergillus niger, and Aspergillus kawachii, and one or more of these may be used. These yeasts, lactic acid bacteria, and koji molds may be commercially available or obtained from depositories, etc., and may be used.

　発酵に供する豆・穀類、果実等の植物は、そのまま使用してもよく、あるいは必要に応じて粉砕、乾燥等の前処理を行ってもよい。また必要に応じて水を添加して希釈してもよい。 Beans, grains, fruits, and other plants to be fermented may be used as is, or may be pretreated by crushing, drying, etc. as necessary. Water may also be added to dilute the product as necessary.

　上記（ａ）～（ｇ）の発酵物は、原料となる植物に、乳酸菌、酵母または麹菌を接種し、培養させることによって得られる。培養は、常法によって行えばよく、例えば、１種または２種以上の植物の混合物に対し、乳酸菌、酵母または麹菌を０．００１～１質量％程度添加し、２０～５０℃で７０～１４０時間程度発酵処理させればよい。 The fermented products (a) to (g) above are obtained by inoculating the plant material with lactic acid bacteria, yeast or koji mold and culturing it. Cultivation can be carried out by a conventional method, for example, by adding about 0.001 to 1% by mass of lactic acid bacteria, yeast or koji mold to a mixture of one or more types of plants, and fermenting it at 20 to 50°C for about 70 to 140 hours.

　このようにして得られた（ａ）～（ｇ）の発酵物を混合してそのまま有効成分とすることもできるが、必要に応じさらに２０～４０℃で２００～３００時間程度培養することが好ましい。さらにこの混合物を後発酵（熟成）させることが好ましい。後発酵は、必要に応じて、酢酸菌を作用させてもよく、例えば、上記（ａ）～（ｇ）に含まれる植物のうち１種または２種以上に上記酵母を作用させたものに、アセトバクター・アセチ(A．aceti）等の酢酸菌を作用させた酢酸発酵物を添加すればよい。後発酵は、２５～３５℃で７０時間～約１年程度行えばよい。後発酵による熟成過程を経ることより、呈味性や製剤性を改善することができ、また抗酸化活性の増大を図ることもできる。 The fermented products (a) to (g) thus obtained can be mixed and used as an active ingredient as is, but it is preferable to further culture the mixture at 20 to 40°C for about 200 to 300 hours if necessary. It is also preferable to post-ferment (maturity) this mixture. Post-fermentation may be performed using acetic acid bacteria if necessary. For example, the above-mentioned yeast may be applied to one or more of the plants included in (a) to (g) above, and an acetic acid fermentation product obtained by applying acetic acid bacteria such as Acetobacter aceti (A. acetate) may be added to the mixture. Post-fermentation may be performed at 25 to 35°C for 70 hours to about one year. The post-fermentation can be performed through a maturation process to improve the taste and formulation properties, and also to increase antioxidant activity.

　上記植物発酵物を製造するための好適な方法の例として、多段階複合発酵方式が挙げられる。この方法は、果実類、野菜類、海藻類を主原料とする複合乳酸菌発酵物と、野菜類、根菜類、種子類、キノコ類、果実類を主要原料とする酵母発酵物を混合し、これに穀類、豆類を主原料とする麹菌発酵物を加え、さらに酢酸発酵物を加え混合した後、ろ過濃縮し、さらに約１年程度の後発酵を行うものである。このような多段階複合発酵によって、それぞれの発酵生産物がさらに別種の菌類によって資化・変換されることにより、風味が向上するとともに、抗酸化活性等の効果が高められると考えられる。 A suitable example of a method for producing the above-mentioned plant fermentation products is the multi-stage complex fermentation method. In this method, a complex lactic acid bacteria fermentation product made primarily from fruits, vegetables, and seaweed is mixed with a yeast fermentation product made primarily from vegetables, root vegetables, seeds, mushrooms, and fruits, to which is added a koji mold fermentation product made primarily from grains and beans, and then an acetic acid fermentation product is added and mixed, after which the mixture is filtered and concentrated, and then post-fermented for about a year. With this type of multi-stage complex fermentation, each fermentation product is further assimilated and converted by different fungi, which is thought to improve the flavor and enhance antioxidant activity and other effects.

　本発明のメタロ－β－ラクタマーゼ阻害剤に用いる有効成分の植物発酵物は、下記（１）から（４）の性質を有する。
（１）呈味性
果物、野菜等原料由来の甘味や有機酸に加え麹由来の甘味を有する。原料由来のポリフェノール類を含むものの苦味は少ない。
（２）水に対する溶解性
水に対して容易に溶解する。
（３）安定性
熱、酸に対して安定であり、ペーストは１年間室温保存しても腐敗や呈味性に変化はない。
（４）安全性
原料に用いた野菜、果物、ハーブ等は日常食しているものであり、また発酵に用いた酵母、乳酸菌、麹菌はいずれも食品の醸造や漬物等に由来する菌種を用いているため食経験が豊富である。 The fermented plant product as an active ingredient used in the metallo-β-lactamase inhibitor of the present invention has the following properties (1) to (4).
(1) Flavor: It has the sweetness derived from the koji in addition to the sweetness and organic acids derived from the fruits and vegetables. Although it contains polyphenols derived from the raw materials, it has little bitterness.
(2) Solubility in Water: Easily soluble in water.
(3) Stability: It is stable against heat and acid, and the paste can be stored at room temperature for one year without spoilage or change in taste.
(4) Safety: The vegetables, fruits, herbs, etc. used as ingredients are commonly consumed, and the yeast, lactic acid bacteria, and koji mold used for fermentation are all species derived from food brewing and pickling, and are therefore widely consumed.

　本発明に用いる植物発酵物は、下記（ア）～（エ）の性質を有する。 The fermented plant product used in the present invention has the following properties (A) to (D).

（ア）一般成分（１００ｇ当たり）
　　水分　　　　　　　１５～３５ｇ
　　たんぱく質　　　　　５～２０ｇ
　　脂質　　　　　　　　１～８ｇ
　　灰分　　　　　　　　１～５ｇ
　　炭水化物　　　　　３０～７０ｇ
　　ナトリウム　　　　４０～１５０ｍｇ
　　ビタミンＢ６　　　　０．１～０．５ｍｇ
　　エネルギー　　　　２００～５００ｋｃａｌ (A) General ingredients (per 100g)
Moisture: 15-35g
Protein: 5-20g
Fat: 1-8g
Ash content: 1-5g
Carbohydrates: 30-70g
Sodium: 40-150mg
Vitamin B6: 0.1-0.5 mg
Energy: 200-500 kcal

（イ）アミノ酸組成（１００ｇ当たり）
　　アルギニン　　　　　　０．２～０．６ｇ
　　リジン　　　　　　　　０．１～０．７ｇ
　　ヒスチジン　　　　　　０．１～０．４ｇ
　　フェニルアラニン　　　０．２～０．８ｇ
　　チロシン　　　　　　　０．１～０．６ｇ
　　ロイシン　　　　　　　０．３～１．２ｇ
　　イソロイシン　　　　　０．２～０．８ｇ
　　メチオニン　　　　　　０．０５～０．３ｇ
　　バリン　　　　　　　　０．２～０．９ｇ
　　アラニン　　　　　　　０．２～０．９ｇ
　　グリシン　　　　　　　０．２～０．７ｇ
　　プロリン　　　　　　　０．４～１．２ｇ
　　グルタミン酸　　　　　１．２～３．０ｇ
　　セリン　　　　　　　　０．２～０．８ｇ
　　スレオニン　　　　　　０．２～０．７ｇ
　　アスパラギン酸　　　　０．４～１．５ｇ
　　トリプトファン　　　　０．０３～０．１５ｇ
　　シスチン　　　　　　　０．０５～０．４０ｇ (a) Amino acid composition (per 100 g)
Arginine 0.2-0.6g
Lysine 0.1-0.7g
Histidine 0.1-0.4g
Phenylalanine 0.2-0.8g
Tyrosine 0.1-0.6g
Leucine 0.3-1.2g
Isoleucine 0.2-0.8g
Methionine 0.05-0.3g
Valine 0.2-0.9g
Alanine 0.2-0.9g
Glycine 0.2-0.7g
Proline 0.4-1.2g
Glutamic acid 1.2-3.0g
Serine 0.2-0.8g
Threonine 0.2-0.7g
Aspartic acid 0.4-1.5g
Tryptophan 0.03-0.15g
Cystine 0.05-0.40g

（ウ）有機酸組成（１００ｇ当たり）
　　クエン酸　　　　　　　０．５～１．２ｇ
　　リンゴ酸　　　　　　　０．０５～０．５ｇ
　　コハク酸　　　　　　　０．０４～０．３ｇ
　　乳酸　　　　　　　　　０．５～６．０ｇ
　　ギ酸　　　　　　　　　０．０１～０．１ｇ
　　ピルビン酸　　　　　　０．００５～０．０５ｇ
　　遊離γ－アミノ酪酸　　０．０１～０．０５ｇ (c) Organic acid composition (per 100 g)
Citric acid: 0.5 to 1.2 g
Malic acid 0.05-0.5g
Succinic acid 0.04-0.3g
Lactic acid 0.5-6.0g
Formic acid 0.01-0.1 g
Pyruvic acid 0.005-0.05g
Free γ-aminobutyric acid 0.01-0.05g

（エ）ミネラル組成（１００ｇ当たり）
　　リン　　　　　　　　１００～４００ｍｇ
　　鉄　　　　　　　　　　　１～５ｍｇ
　　カルシウム　　　　　５００～９００ｍｇ
　　カリウム　　　　　　６００～１０００ｍｇ
　　マグネシウム　　　　　７０～１２０ｍｇ
　　亜鉛　　　　　　　　　　０．８～１．６ｍｇ
　　ヨウ素　　　　　　　　　１．０～２．５ｍｇ (D) Mineral composition (per 100g)
Phosphorus 100-400mg
Iron 1-5mg
Calcium: 500-900mg
Potassium: 600-1,000 mg
Magnesium: 70-120 mg
Zinc 0.8-1.6 mg
Iodine 1.0-2.5mg

　上記植物発酵物は、メタロ－β－ラクタマーゼ阻害作用を有するため、これを有効成分とすることによりメタロ－β－ラクタマーゼ阻害剤とすることができる。植物発酵物が阻害できるメタロ－β－ラクタマーゼは、特に限定されず、ＮＤＭ型メタロ－β－ラクタマーゼ、ＩＭＰ型メタロ－β－ラクタマーゼ等が挙げられるが、好ましくは、世界的な地理的拡散ならびに各種病原菌を含む腸内細菌科細菌への異菌種間拡散が懸念されているＮＤＭ型メタロ－β－ラクタマーゼである。 The above-mentioned plant fermentation product has a metallo-β-lactamase inhibitory effect, and therefore can be used as a metallo-β-lactamase inhibitor by using it as an active ingredient. There are no particular limitations on the metallo-β-lactamase that can be inhibited by the plant fermentation product, and examples include NDM-type metallo-β-lactamase and IMP-type metallo-β-lactamase, but preferably NDM-type metallo-β-lactamase, which is of concern for its global geographical spread and its spread between different bacterial species to Enterobacteriaceae bacteria, including various pathogenic bacteria.

　以上説明した植物発酵物は、メタロ－β－ラクタマーゼの阻害作用を有しているため、メタロ－β－ラクタマーゼ阻害剤として利用することができる。なお、植物発酵物がメタロ－β－ラクタマーゼの阻害作用を有しているかどうかは、実施例に記載の試験で確認することができる。また、上記植物発酵物のメタロ－β－ラクタマーゼの阻害作用は、タンパク量にして概ね２０μｇ以上、好ましくは３０～６０μｇにおいて抗菌薬数μｇと相乗効果を示す。 The plant fermentation products described above have an inhibitory effect on metallo-β-lactamase, and therefore can be used as metallo-β-lactamase inhibitors. Whether or not a plant fermentation product has an inhibitory effect on metallo-β-lactamase can be confirmed by the tests described in the Examples. Furthermore, the metallo-β-lactamase inhibitory effect of the plant fermentation product described above shows a synergistic effect with several μg of an antibiotic when the protein amount is approximately 20 μg or more, preferably 30 to 60 μg.

　本発明のメタロ－β－ラクタマーゼ阻害剤は、上記植物発酵物をそのまま用いても、あるいは、公知の製剤学的製法に準じて、薬理学的に許容され得る担体、賦形剤、水分活性調整剤等を加え、製剤化してもよい。植物発酵物は、必要に応じ濃縮して濃度を調整したり、噴霧または凍結乾燥等により粉末化してもよい。製剤化において用いられる担体や賦形剤としては、たとえば乳糖、ブドウ糖、蔗糖、デンプン、糖類混合物等が用いられる。最終的形態としては、溶液、ペースト、ソフトカプセル、チュアブル、カプセル、散剤、顆粒剤、シロップ、内服液剤、スプレー剤、軟膏、クリーム、外用液剤、点眼剤、点鼻剤、座剤、貼付剤等が挙げられる。用量・用法としては、例えば、有効成分の植物発酵物として大人１日当たり、０．１ｇ以上、好ましくは０．１～１２ｇ、より好ましくは０．６～１０ｇ（固形分換算）程度経口摂取すればよい。このような植物発酵物を製剤化、食品の形態とした市販品として、天生酵素金印、天生酵素カプセル、あもう酵素（何れも日本自然発酵社製）等が挙げられる。 The metallo-β-lactamase inhibitor of the present invention may be prepared by using the above-mentioned plant fermentation product as it is, or by adding pharmacologically acceptable carriers, excipients, water activity regulators, etc. according to known pharmaceutical manufacturing methods. The plant fermentation product may be concentrated to adjust the concentration as necessary, or may be powdered by spraying or freeze-drying. Examples of carriers and excipients used in formulation include lactose, glucose, sucrose, starch, and sugar mixtures. Examples of final forms include solutions, pastes, soft capsules, chewable tablets, capsules, powders, granules, syrups, oral liquids, sprays, ointments, creams, external liquids, eye drops, nasal drops, suppositories, and patches. As for dosage and method of use, for example, 0.1 g or more, preferably 0.1 to 12 g, and more preferably 0.6 to 10 g (in terms of solid content) of the plant fermentation product as the active ingredient may be orally taken by an adult per day. Examples of commercially available products in which such plant fermentation products have been formulated and made into food products include Tensei Koso Kinjirushi, Tensei Koso Capsules, and Amou Koso (all manufactured by Nihon Shizen Hakkou Co., Ltd.).

　本発明のメタロ－β－ラクタマーゼ阻害剤は、多剤耐性グラム陰性菌関連疾患の動物、好ましくは多剤耐性グラム陰性菌関連疾患のヒトを除く動物に、抗菌薬と共に投与することにより、多剤耐性グラム陰性菌関連疾患を治療することができる。多剤耐性グラム陰性菌関連疾患としては、特に限定されないが、例えば生命に関わる重篤なものとしては肺炎や敗血症等の疾患が挙げられる。また、抗菌薬としては、特に限定されないが、例えば、ベンジルペニシリンカリウム（PCG）、オキサシリンナトリウム（MPIPC）、アンピシリンナトリウム（ABPC）、アモキシシリン（AMPC）、ピペラシリンナトリウム（PIPC）、トシル酸スルタミシリン（SBTPC）等のペニシリン系抗菌薬、セファロチンナトリウム（CET）、セファゾリンナトリウム（CEZ）、塩酸セフォチアム（CTM）、セフォペラゾンナトリウム（CPZ）、セフォタキシムナトリウム（CTX）、セフチゾキシムナトリウム（CZX）、塩酸セフメノキシム（CMX）、セフタジジム（CAZ）、セフトリアキソンナトリウム（CTRX）、硫酸セフピロム（CPR）、塩酸セフェピム（CFPM）、塩酸セフォゾプラン（CZOP）、セファレキシン（CEX）、セファクロル（CCL）、セフロキサジン（CXD）、セフィキシム（CFIX）、セフチブテン（CETB）、セフジニル（CFDN）、セフロキシムナトリウム（CXM）、セフポドキシムナトリウム（CPDX）、塩酸セフテラム（CFTM）、セフカペンナトリウム（CFPN）、セフジトレンナトリウム（CDTR）等のセフェム系抗菌薬、イミペネム（IPM）、メロペネム三水和物（MEPM）、ビアペネム（BIPM）、ドリペネム水和物（DRPM）、テビペネム水和物（TBPM）等のカルバペネム系抗菌薬等が挙げられる。 The metallo-β-lactamase inhibitor of the present invention can be administered together with an antibacterial agent to animals with a multidrug-resistant gram-negative bacteria-associated disease, preferably animals other than humans with a multidrug-resistant gram-negative bacteria-associated disease, to treat the multidrug-resistant gram-negative bacteria-associated disease. There are no particular limitations on the multidrug-resistant gram-negative bacteria-associated disease, but examples of serious, life-threatening diseases include pneumonia and sepsis. In addition, examples of the antibacterial agent include, but are not limited to, penicillin-based antibacterial agents such as benzylpenicillin potassium (PCG), oxacillin sodium (MPIPC), ampicillin sodium (ABPC), amoxicillin (AMPC), piperacillin sodium (PIPC), and sultamicillin tosylate (SBTPC); cephalothin sodium (CET), cefazolin sodium (CEZ), cefotiam hydrochloride (CTM), cefoperazone sodium (CPZ), cefotaxime sodium (CTX), ceftizoxime sodium (CZX), cefmenoxime hydrochloride (CMX), ceftazidime (CAZ), ceftriaxone sodium (CTRX), and cefpirimidazole sulfate (CTRX). These include cephem antibiotics such as cephalosporin (CPR), cefepime hydrochloride (CFPM), cefozopran hydrochloride (CZOP), cephalexin (CEX), cefaclor (CCL), cefroxadine (CXD), cefixime (CFIX), ceftibuten (CETB), cefdinir (CFDN), cefuroxime sodium (CXM), cefpodoxime sodium (CPDX), cefteram hydrochloride (CFTM), cefcapene sodium (CFPN), and cefditoren sodium (CDTR); and carbapenem antibiotics such as imipenem (IPM), meropenem trihydrate (MEPM), biapenem (BIPM), doripenem hydrate (DRPM), and tebipenem hydrate (TBPM).

　本発明のメタロ－β－ラクタマーゼ阻害剤を多剤耐性グラム陰性菌関連疾患の動物に投与する方法は特に限定されず、外用、内服の何れでもよい。 The method of administering the metallo-β-lactamase inhibitor of the present invention to animals with multidrug-resistant gram-negative bacteria-associated diseases is not particularly limited, and may be either topical or oral administration.

　本発明のメタロ－β－ラクタマーゼ阻害剤は、多剤耐性グラム陰性菌の耐性機構を阻害し、既存の抗菌薬が効果を発揮することができる。そのため、多剤耐性グラム陰性菌に、抗菌薬と、本発明のメタロ－β－ラクタマーゼ阻害剤を投与することより、多剤耐性グラム陰性菌を制御することができる。ここで多剤耐性グラム陰性菌とは、上記した抗菌薬に耐性を有していて抗菌薬により生育が阻害されないグラム陰性菌のことをいう。 The metallo-β-lactamase inhibitor of the present invention inhibits the resistance mechanism of multidrug-resistant gram-negative bacteria, allowing existing antibacterial drugs to be effective. Therefore, by administering an antibacterial drug and the metallo-β-lactamase inhibitor of the present invention to multidrug-resistant gram-negative bacteria, the multidrug-resistant gram-negative bacteria can be controlled. Here, multidrug-resistant gram-negative bacteria refers to gram-negative bacteria that are resistant to the above-mentioned antibacterial drugs and whose growth is not inhibited by the antibacterial drugs.

　上記した多剤耐性グラム陰性菌関連疾患の治療や、多剤耐性グラム陰性菌の制御には、本発明のメタロ－β－ラクタマーゼ阻害剤と上記抗菌薬を含有させた抗多剤耐性グラム陰性菌用組成物を利用してもよい。この組成物における抗菌薬の含有量は特に限定されず、通常抗菌薬が効果を発揮する量であればよい。 For the treatment of the above-mentioned multidrug-resistant gram-negative bacteria-related diseases and for the control of multidrug-resistant gram-negative bacteria, a composition for use against multidrug-resistant gram-negative bacteria containing the metallo-β-lactamase inhibitor of the present invention and the above-mentioned antibacterial agent may be used. The content of the antibacterial agent in this composition is not particularly limited, and may be any amount at which the antibacterial agent is normally effective.

　上記した本発明の抗多剤耐性グラム陰性菌用組成物は、本発明のメタロ－β－ラクタマーゼ阻害剤と同様に、製剤化することができる。最終的形態としては、本発明のメタロ－β－ラクタマーゼ阻害剤と同様に、溶液、ペースト、ソフトカプセル、チュアブル、カプセル、散剤、顆粒剤、シロップ、内服液剤、スプレー剤、軟膏、クリーム、外用液剤、点眼剤、点鼻剤、座剤、貼付剤等が挙げられる。 The anti-multidrug resistant Gram-negative bacteria composition of the present invention described above can be formulated in the same manner as the metallo-β-lactamase inhibitor of the present invention. The final form may be a solution, paste, soft capsule, chewable tablet, capsule, powder, granule, syrup, oral liquid, spray, ointment, cream, topical liquid, eye drops, nasal drops, suppositories, patches, etc., in the same manner as the metallo-β-lactamase inhibitor of the present invention.

　なお、本発明のメタロ－β－ラクタマーゼ阻害剤は食経験の長い食品成分でもあるため、抗多剤耐性グラム陰性菌用食品として利用することができる。この食品は、従来の公知の食品の原料あるいは調味料の一部として本発明のメタロ－β－ラクタマーゼ阻害剤の有効成分である植物発酵物を用いるだけでよい。具体的な食品としては、例えば、みそ等の調味料、食パン等のパン類、せんべい、クッキー、チョコレート、飴、饅頭、ケーキ等の菓子類、ヨーグルト、チーズ等乳製品、たくわん等の漬物類、ラーメン、そば、うどん等の麺類、コーンポタージュ、わかめスープ等のスープ類、清涼飲料、健康飲料、炭酸飲料、果汁飲料等が挙げられる。 The metallo-β-lactamase inhibitor of the present invention is also a food ingredient that has a long history of use in food, and can therefore be used as a food for anti-multidrug-resistant gram-negative bacteria. This food can be made by simply using the plant fermentation product, which is the active ingredient of the metallo-β-lactamase inhibitor of the present invention, as part of a conventional food ingredient or seasoning. Specific examples of foods include seasonings such as miso, breads such as white bread, confectioneries such as rice crackers, cookies, chocolate, candy, buns, and cakes, dairy products such as yogurt and cheese, pickles such as takuan, noodles such as ramen, soba, and udon, soups such as corn potage and wakame seaweed soup, soft drinks, health drinks, carbonated drinks, and fruit juice drinks.

　以下、本発明の実施例を挙げて本発明を詳細に説明するが本発明はこれら実施例に何ら限定されるものではない。 The present invention will be described in detail below with reference to examples, but the present invention is not limited to these examples.

製　造　例　１
　　　植物発酵物の製造：
　以下の植物を原料として使用した。
（ａ）豆・穀類（大麦、黒大豆、赤米、黒米、小豆、はと麦、ヒエ、アワ、キビ）
（ｂ）果実類（ミカン、ブドウ、リンゴ、ヤマブドウ、モモ、カキ、パパイヤ、ナシ、スイカ、ウメ、イチジク、カリン、カボチャ、キンカン、ユズ、ビワ、アンズ、ナツメ、クリ、マタタビ、スモモ）
（ｃ）根菜類（紫イモ、菊芋、ニンジン、タマネギ、サツマイモ、里芋、自然薯、大根、赤カブ、ゴボウ、レンコン、ヤーコン、ユリ根、クワイ、しょうが、にんにく、ウコン）
（ｄ）花・葉菜類（キャベツ、紫蘇、桑葉、どくだみ、ヨモギ、クマザサ、タンポポ）
（ｅ）海草類（コンブ、ワカメ、モズク）
（ｆ）種子類（黒ゴマ、クルミ、ギンナン）
（ｇ）キノコ類（マイタケ、シイタケ） Manufacturing Example 1
Production of plant fermentation products:
The following plants were used as raw materials:
(a) Beans and grains (barley, black soybeans, red rice, black rice, adzuki beans, pearl barley, barnyard millet, foxtail millet, and millet)
(b) Fruits (tangerines, grapes, apples, wild grapes, peaches, persimmons, papayas, pears, watermelons, plums, figs, quince, pumpkins, kumquats, yuzu, loquats, apricots, jujubes, chestnuts, silver vines, and plums)
(c) Root vegetables (purple sweet potato, Jerusalem artichoke, carrot, onion, sweet potato, taro, wild yam, radish, red turnip, burdock, lotus root, yacon, lily root, water chestnut, ginger, garlic, turmeric)
(d) Flowers and leafy vegetables (cabbage, shiso, mulberry leaves, dokudami, mugwort, kumazasa, dandelion)
(e) Seaweed (kelp, wakame, mozuku)
(f) Seeds (black sesame, walnuts, ginkgo nuts)
(g) Mushrooms (maitake, shiitake)

　上記（ｃ）、（ｄ）および（ｇ）の原料（７３０ｇ）に対し、乳酸菌類（P. acidilacti, L. brevis, L. mesenteroides, L. plantarum, L. lactis, L. sakei, L. casei）が約１．０×１０５ｃｆｕ／ｇの菌濃度となるように調製した培養液を０．２質量％接種し、３０℃で５０時間培養を行った。また上記（ｂ）、（ｅ）および（ｆ）の原料（９００ｋｇ）に対し、酵母類（S. cervisiae ５種、Z. rouxii ２種）が約１．０×１０５ｃｆｕ／ｇの菌濃度となるように調製した培養液を０．４質量％接種し３０℃で５０時間培養を行った。（ａ）豆類および穀類系原料（１０００ｋｇ）には、麹菌類（黄麹菌、黒麹菌、白麹菌）を０．１質量％接種して３５℃で７０時間培養を行った。次いでそれぞれの培養物を混合後、３０℃で２００時間培養を行った。発酵を終了したモロミについて固液分離操作を行い、得られた濾液を濃縮してペースト状にしたものを容器に分注し、更に１年間後発酵（熟成）させ植物発酵物を得た。 The above raw materials (c), (d) and (g) (730 g) were inoculated with 0.2% by mass of a culture solution prepared so that lactic acid bacteria (P. acidilacti, L. brevis, L. mesenteroides, L. plantarum, L. lactis, L. sakei, L. casei) had a bacterial concentration of about 1.0 x 105 cfu/g, and cultured for 50 hours at 30°C. The above raw materials (b), (e) and (f) (900 kg) were inoculated with 0.4% by mass of a culture solution prepared so that yeasts (5 species of S. cervisiae, 2 species of Z. rouxii) had a bacterial concentration of about 1.0 x 105 cfu/g, and cultured for 50 hours at 30°C. (a) Bean and cereal raw materials (1000 kg) were inoculated with 0.1% by mass of koji mold (yellow koji mold, black koji mold, white koji mold) and cultured for 70 hours at 35° C. Then, the cultures were mixed and cultured for 200 hours at 30° C. The fermented moromi was subjected to solid-liquid separation, and the obtained filtrate was concentrated into a paste, which was dispensed into containers and further fermented (aged) for one year to obtain a plant fermentation product.

　製造例１で得られた植物発酵物は以下の性質を有するものであった。
（ア）一般分析値（１００ｇ当たり）
　　水分　　　　　２５．２ｇ
　　たんぱく質　　１１．８ｇ
　　脂質　　　　　　３．６ｇ
　　灰分　　　　　　２．１ｇ
　　炭水化物　　　５７．３ｇ
　　ナトリウム　　５４．０ｍｇ
　　ビタミンＢ６　　０．２０ｍｇ
　　エネルギー　　３０９ｋｃａｌ The plant fermentation product obtained in Production Example 1 had the following properties.
(A) General analysis value (per 100g)
Water 25.2g
Protein: 11.8g
Fat 3.6g
Ash content: 2.1g
Carbohydrates: 57.3g
Sodium 54.0mg
Vitamin B6 0.20mg
Energy 309kcal

（イ）アミノ酸組成（１００ｇ当たり）
　試料を６規定塩酸で加水分解したものをアミノ酸自動分析計によって分析した。シスチンについては過蟻酸酸化処理後、塩酸加水分解を用いた。トリプトファンは高速液体クロマト法を用いた。
　　アルギニン　　　　　　０．３３ｇ
　　リジン　　　　　　　　０．３４ｇ
　　ヒスチジン　　　　　　０．２２ｇ
　　フェニルアラニン　　　０．５１ｇ
　　チロシン　　　　　　　０．３２ｇ
　　ロイシン　　　　　　　０．７４ｇ
　　イソロイシン　　　　　０．４２ｇ
　　メチオニン　　　　　　０．１３ｇ
　　バリン　　　　　　　　０．５４ｇ
　　アラニン　　　　　　　０．４８ｇ
　　グリシン　　　　　　　０．４２ｇ
　　プロリン　　　　　　　０．９２ｇ
　　グルタミン酸　　　　　２．２５ｇ
　　セリン　　　　　　　　０．４ｇ
　　スレオニン　　　　　　０．３６ｇ
　　アスパラギン酸　　　　０．８４ｇ
　　トリプトファン　　　　０．０６ｇ
　　シスチン　　　　　　　０．１５ｇ (a) Amino acid composition (per 100 g)
The samples were hydrolyzed with 6N hydrochloric acid and analyzed by an automatic amino acid analyzer. Cystine was analyzed by hydrolysis with hydrochloric acid after oxidation with performic acid. Tryptophan was analyzed by high performance liquid chromatography.
Arginine 0.33g
Lysine 0.34g
Histidine 0.22g
Phenylalanine 0.51g
Tyrosine 0.32g
Leucine 0.74g
Isoleucine 0.42g
Methionine 0.13g
Valine 0.54g
Alanine 0.48g
Glycine 0.42g
Proline 0.92g
Glutamic acid 2.25g
Serine 0.4g
Threonine 0.36g
Aspartic acid 0.84g
Tryptophan 0.06g
Cystine 0.15g

（ウ）有機酸組成（１００ｇ当たり）
　　クエン酸　　　　　　　０．８１ｇ
　　リンゴ酸　　　　　　　０．３１ｇ
　　コハク酸　　　　　　　０．１２ｇ
　　乳酸　　　　　　　　　１．１７ｇ
　　ギ酸　　　　　　　　　０．０３ｇ
　　ピルビン酸　　　　　　０．０１ｇ
　　遊離γ－アミノ酪酸　　　２４ｍｇ (c) Organic acid composition (per 100 g)
Citric acid 0.81g
Malic acid 0.31g
Succinic acid 0.12g
Lactic acid 1.17g
Formic acid 0.03g
Pyruvic acid 0.01g
Free γ-aminobutyric acid 24mg

（エ）ミネラル組成（１００ｇ当たり）
　　リン　　　　　　　２６２ｍｇ
　　鉄　　　　　　　　　　２．６５ｍｇ
　　カルシウム　　　　　７２．１ｍｇ
　　カリウム　　　　　７９８ｍｇ
　　マグネシウム　　　　９７．８ｍｇ
　　亜鉛　　　　　　　　　１．１９ｍｇ
　　ヨウ素　　　　　　　　１．７ｍｇ (D) Mineral composition (per 100g)
Phosphorus 262mg
Iron 2.65mg
Calcium 72.1mg
Potassium 798mg
Magnesium 97.8mg
Zinc 1.19mg
Iodine 1.7mg

　この植物発酵物は、天生酵素金印（日本自然発酵社製）と同様のものであり、これを以下の実施例で用いた。 This plant fermentation product is the same as Tensei Koso Kinjirushi (manufactured by Nihon Shizen Hakko Co., Ltd.), and was used in the following examples.

実　施　例　１
　　　製造例１で調製した植物発酵物の物性：
（１）最小発育阻止濃度の測定
　製造例１で調製した植物発酵物を秤量し、その２倍の滅菌水を添加し、一夜浸透して成分を溶出させ、遠心分離後の上清を０．２２μｍのフィルターで濾過したものを試料とした。この試料を用いて、多剤耐性グラム陰性菌に対するＭＩＣを調べた。 Example 1
Properties of the fermented plant product prepared in Production Example 1:
(1) Measurement of minimum inhibitory concentration The plant fermentation product prepared in Production Example 1 was weighed, and twice the amount of sterilized water was added, and the mixture was left to soak overnight to elute the components. After centrifugation, the supernatant was filtered through a 0.22 μm filter to prepare a sample. Using this sample, the MIC against multidrug-resistant Gram-negative bacteria was examined.

　この結果より、植物発酵物の多剤耐性グラム陰性菌に対するＭＩＣは１／４濃度であった。 These results showed that the MIC of the fermented plant product against multidrug-resistant gram-negative bacteria was 1/4 the concentration.

（２）コンビネーション試験
　各種抗菌薬の濃度勾配系列を固相してある薬剤感受性試験プレート（ドライプレート栄研：栄研化学製）と多剤耐性グラム陰性菌を用いてコンビネーション試験を行った。その結果を図２に示した。なお、各プレートには植物発酵物（試料）を０、１／１０または１／１６で添加し、多剤耐性グラム陰性菌を一定量添加した。 (2) Combination test A combination test was performed using a drug susceptibility test plate (Dry Plate Eiken: Eiken Chemical Co., Ltd.) on which a concentration gradient series of various antibacterial drugs was immobilized and multidrug-resistant gram-negative bacteria. The results are shown in Figure 2. Each plate was added with 0, 1/10 or 1/16 of the plant fermentation product (sample), and a fixed amount of multidrug-resistant gram-negative bacteria.

　この結果より、抗菌薬単独では多剤耐性グラム陰性菌に効果が認められなかったが、植物発酵物をＭＩＣより低い１／８～１／１０で添加することにより、メロペネムやドリペネムといったカルバペネム系、さらにはセフェピムなどセフェム系抗菌薬において多剤耐性グラム陰性菌の発育が阻止されＭＩＣが大きく低下した。 These results showed that antibiotics alone were not effective against multidrug-resistant gram-negative bacteria, but by adding plant fermentation products at 1/8 to 1/10 of the MIC, carbapenem antibiotics such as meropenem and doripenem, and cephem antibiotics such as cefepime, the growth of multidrug-resistant gram-negative bacteria was inhibited, and the MIC was significantly reduced.

（３）チェッカーボードアッセイ
　コンビネーション試験において比較的再現性の高いメロペネム(MEPM)およびドリペネム(DRPM)について、植物発酵物の併用効果を確認するためチェッカーボード試験を行った。チェッカーボード試験は、９６穴プレートに抗菌薬と植物発酵物を濃度勾配をつけて割り振り、多剤耐性グラム陰性菌を加えて一晩培養し、各ウエルでFIC indexを算出して併用効果を判定した。チェッカーボード試験の結果を図３に示した。なお、相乗/相加効果の判定には、下記計算式によりFIC index（fractional inhibitory concentration）を求め、０．５以下を“相乗効果あり”と判定した。 (3) Checkerboard assay A checkerboard test was performed to confirm the combined effect of meropenem (MEPM) and doripenem (DRPM), which have relatively high reproducibility in combination tests, with the plant fermentation product. In the checkerboard test, antibiotics and plant fermentation products were allocated in a concentration gradient to a 96-well plate, multidrug-resistant gram-negative bacteria were added and cultured overnight, and the FIC index was calculated for each well to determine the combined effect. The results of the checkerboard test are shown in Figure 3. To determine the synergistic/additive effect, the FIC index (fractional inhibitory concentration) was calculated using the following formula, and a value of 0.5 or less was determined to be "synergistic."

Figure JPOXMLDOC01-appb-M000001
Figure JPOXMLDOC01-appb-M000001

　この結果より、抗菌薬単独では多剤耐性グラム陰性菌に効果が認められなかったが、植物発酵物を１／８～１／１０で添加することにより、メロペネムやドリペネムといったカルバペネム系、さらにはセフェピムなどセフム系抗菌薬において多剤耐性グラム陰性菌の発育が阻止されMICが大きく低下した。 These results showed that antibiotics alone were not effective against multidrug-resistant gram-negative bacteria, but by adding 1/8 to 1/10 of the plant fermentation product, the growth of multidrug-resistant gram-negative bacteria was inhibited and the MIC was significantly reduced for carbapenem antibiotics such as meropenem and doripenem, and also cefepime and other cefepime antibiotics.

（４）ニトロセフィン試験
　メタロ－β－ラクタマーゼの活性を調べるため常法（石井良和ら、「喀痰中β－ラクタマーゼ活性の測定方法の確立に関する検討」、日本化学療法学会雑誌、Vol.47, No.10，p619-622（1999））に従ってニトロセフィン試験を行った。植物発酵物（図中：発酵液）の存在下でニトロセフィンの分解による赤色発色が陽性対照に比べて抑制されたため、メタロ－β－ラクタマーゼの活性が低下したことによりカルバペネム系など既存の抗菌薬が効力を発揮した（図４）。なお、メルカプト酢酸とは従来から知られている試験管内でのメタロ－β－ラクタマーゼ阻害剤である。 (4) Nitrocefin test To examine the activity of metallo-β-lactamase, a nitrocefin test was performed according to a standard method (Ishii Yoshikazu et al., "Study on the establishment of a method for measuring β-lactamase activity in sputum," Journal of the Japanese Society of Chemotherapy, Vol. 47, No. 10, p. 619-622 (1999)). In the presence of plant fermentation products (fermentation liquid in the figure), the red color development due to the decomposition of nitrocefin was suppressed compared to the positive control, indicating that existing antibacterial drugs such as carbapenems were effective due to the reduced activity of metallo-β-lactamase (Figure 4). Mercaptoacetic acid is a known metallo-β-lactamase inhibitor in vitro.

実　施　例　２
　　　抗多剤耐性グラム陰性菌用組成物の調製：
　実施例１で調製した植物発酵物の１０ｇと抗菌薬（メロペネム）０．５ｇを混合し、これを水で希釈した後、味を調整して、液状の抗多剤耐性グラム陰性菌用組成物を調製した。 Example 2
Preparation of a composition for use against multidrug-resistant Gram-negative bacteria:
10 g of the plant fermentation product prepared in Example 1 was mixed with 0.5 g of an antibiotic (meropenem), diluted with water, and the taste was adjusted to prepare a liquid composition against multidrug-resistant gram-negative bacteria.

実　施　例　３
　　　抗多剤耐性グラム陰性菌用組成物の調製：
　実施例１で調製した植物発酵物の１０ｇと抗菌薬（メロペネム）０．５ｇを混合して、ペースト状の抗多剤耐性グラム陰性菌用組成物を調製した。 Example 3
Preparation of a composition for use against multidrug-resistant Gram-negative bacteria:
A paste-like composition for anti-multidrug-resistant gram-negative bacteria was prepared by mixing 10 g of the plant fermentation product prepared in Example 1 with 0.5 g of an antibacterial agent (meropenem).

実　施　例　４
　　　抗多剤耐性グラム陰性菌用食品（みそ様食品）：
　製造例１で製造した植物発酵物とみそを混合し、調味料で味を調整して抗多剤耐性グラム陰性菌用食品（みそ様食品）を製造した。 Example 4
Food for anti-multidrug resistant gram-negative bacteria (miso-like food):
The plant fermented product produced in Production Example 1 was mixed with miso, and the taste was adjusted with seasonings to produce a food for multidrug-resistant gram-negative bacteria (miso-like food).

実　施　例　５
　　　抗多剤耐性グラム陰性菌用食品（飲料）：
　製造例１で製造した植物発酵物を水に溶解した後、果糖ブドウ糖液と果汁を混合し、味を調整して抗多剤耐性グラム陰性菌用食品（飲料）を製造した。 Example 5
Foods (drinks) for anti-multidrug resistant gram-negative bacteria:
The plant fermentation product produced in Production Example 1 was dissolved in water, and then mixed with fructose glucose liquid and fruit juice, and the taste was adjusted to produce a food (drink) for use against multidrug-resistant gram-negative bacteria.

実　施　例　６
　　　抗多剤耐性グラム陰性菌用食品（ソフトカプセル）：
　製造例１で製造した植物発酵物と、植物油、レシチンを混合したものを常法でソフトカプセルに充填して抗多剤耐性グラム陰性菌用食品（ソフトカプセル）を製造した。 Example 6
Food for anti-multidrug resistant gram-negative bacteria (soft capsule):
The plant fermentation product produced in Production Example 1 was mixed with vegetable oil and lecithin and filled into soft capsules in a conventional manner to produce a food product (soft capsule) against multidrug-resistant gram-negative bacteria.

実　施　例　７
　　　抗多剤耐性グラム陰性菌用食品（チュアブル錠）：
　製造例１で製造した植物発酵物と、結晶セルロース、白糖を混合したものを常法で打錠してＱＯＬ改善に用いられる抗多剤耐性グラム陰性菌用食品（チュアブル錠）を製造した。 Example 7
Food for anti-multidrug resistant gram-negative bacteria (chewable tablets):
The plant fermentation product produced in Production Example 1 was mixed with crystalline cellulose and sucrose and tableted in a conventional manner to produce an anti-multidrug resistant Gram-negative bacteria food (chewable tablet) for use in improving QOL.

実　施　例　８
　　　抗多剤耐性グラム陰性菌用食品（ソフトカプセル）：
　製造例１で製造した植物発酵物（一日分量）と、植物油、レシチンおよびアンセリン９００ｍｇを混合したものを常法でソフトカプセルに充填して抗多剤耐性グラム陰性菌用食品（ソフトカプセル）を製造した。 Example 8
Food for anti-multidrug resistant gram-negative bacteria (soft capsule):
The plant fermentation product (daily amount) produced in Production Example 1 was mixed with vegetable oil, lecithin and 900 mg of anserine and filled into soft capsules in a conventional manner to produce a food product (soft capsule) against multidrug-resistant gram-negative bacteria.

　本発明のメタロ－β－ラクタマーゼ阻害剤は、多剤耐性グラム陰性菌の耐性機構を阻害し、抗菌薬が効果を発揮できるため、多剤耐性グラム陰性菌に関連する疾患を治療するのに利用することができる。
 
　　　　　　　　　　　　　　　　　　　　　　　　　　以　　上 The metallo-β-lactamase inhibitor of the present invention inhibits the resistance mechanism of multidrug-resistant gram-negative bacteria, enabling antibacterial drugs to be effective, and can therefore be used to treat diseases associated with multidrug-resistant gram-negative bacteria.

that's all

Claims (9)

　次の（ａ）～（ｇ）
（ａ）大麦、黒大豆、赤米、黒米、小豆、はと麦、ヒエ、アワおよびキビからなる豆・穀物類の麹菌発酵物
（ｂ）ミカン、ブドウ、リンゴ、ヤマブドウ、モモ、カキ、パパイヤ、ナシ、スイカ、ウメ、イチジク、カリン、カボチャ、キンカン、ユズ、ビワ、アンズ、ナツメ、クリ、マタタビおよびスモモからなる果実類の酵母および／又は乳酸菌発酵物
（ｃ）紫イモ、菊芋、ニンジン、タマネギ、サツマイモ、里芋、自然薯、大根、赤カブ、ゴボウ、レンコン、ヤーコン、ユリ根、クワイ、しょうが、にんにくおよびウコンからなる根菜類・イモ類の酵母および／又は乳酸菌発酵物
（ｄ）キャベツ、紫蘇、桑葉、どくだみ、ヨモギ、クマザサおよびタンポポからなる花・葉菜類の酵母および／又は乳酸菌発酵物
（ｅ）コンブ、ワカメおよびモズクからなる海藻類の酵母および／又は乳酸菌発酵物
（ｆ）黒ゴマ、クルミおよびギンナンからなる種子類の酵母および／又は乳酸菌発酵物
（ｇ）マイタケおよびシイタケからなるキノコ類の酵母および／又は乳酸菌発酵物
の混合物である植物発酵物を有効成分として含有するメタロ－β－ラクタマーゼ阻害剤。 The following (a) to (g):
(a) Aspergillus oryzae fermentation products of beans and grains including barley, black soybeans, red rice, black rice, red beans, pearl barley, barnyard millet, foxtail millet, and millet; (b) yeast and/or lactic acid bacteria fermentation products of fruits including mandarin oranges, grapes, apples, wild grapes, peaches, persimmons, papayas, pears, watermelons, plums, figs, quince, pumpkins, kumquats, yuzu, loquats, apricots, jujubes, chestnuts, silver vine, and plums; (c) purple sweet potatoes, Jerusalem artichokes, carrots, onions, sweet potatoes, taro, wild yams, radishes, red turnips, burdock, lotus root, yacon, lily root, water chestnut, ginger, garlic, and turmeric. (d) yeast and/or lactic acid bacteria fermentation products of flower and leaf vegetables including cabbage, shiso, mulberry leaves, dokudami, mugwort, kumazasa, and dandelion; (e) yeast and/or lactic acid bacteria fermentation products of seaweed including kombu, wakame, and mozuku; (f) yeast and/or lactic acid bacteria fermentation products of seeds including black sesame, walnuts, and ginkgo nuts; and (g) a plant fermentation product which is a mixture of yeast and/or lactic acid bacteria fermentation products of mushrooms including maitake and shiitake mushrooms. 　植物発酵物が、植物発酵物１００ｇ当たり以下の組成のアミノ酸を含有するものである請求項１に記載のメタロ－β－ラクタマーゼ阻害剤。
　　アルギニン　　　　　　　　０．２～０．６ｇ
　　リジン　　　　　　　　　　０．１～０．７ｇ
　　ヒスチジン　　　　　　　　０．１～０．４ｇ
　　フェニルアラニン　　　　　０．２～０．８ｇ
　　チロシン　　　　　　　　　０．１～０．６ｇ
　　ロイシン　　　　　　　　　０．３～１．２ｇ
　　イソロイシン　　　　　　　０．２～０．８ｇ
　　メチオニン　　　　　　　　０．０５～０．３０ｇ
　　バリン　　　　　　　　　　０．２～０．９ｇ
　　アラニン　　　　　　　　　０．２～０．９ｇ
　　グリシン　　　　　　　　　０．２～０．７ｇ
　　プロリン　　　　　　　　　０．４～１．２ｇ
　　グルタミン酸　　　　　　　１．２～３．０ｇ
　　セリン　　　　　　　　　　０．２～０．８ｇ
　　スレオニン　　　　　　　　０．２～０．７ｇ
　　アスパラギン酸　　　　　　０．４～１．５ｇ
　　トリプトファン　　　　　　０．０３～０．１５ｇ
　　シスチン　　　　　　　　　０．０５～０．４０ｇ The metallo-β-lactamase inhibitor according to claim 1, wherein the plant fermentation product contains amino acids having the following composition per 100 g of the plant fermentation product:
Arginine 0.2-0.6g
Lysine 0.1-0.7g
Histidine 0.1-0.4g
Phenylalanine 0.2-0.8g
Tyrosine 0.1-0.6g
Leucine 0.3-1.2g
Isoleucine 0.2-0.8g
Methionine 0.05-0.30g
Valine 0.2-0.9g
Alanine 0.2-0.9g
Glycine 0.2-0.7g
Proline 0.4-1.2g
Glutamic acid 1.2-3.0g
Serine 0.2-0.8g
Threonine 0.2-0.7g
Aspartic acid 0.4-1.5g
Tryptophan 0.03-0.15g
Cystine 0.05-0.40g 　植物発酵物が、植物発酵物１００ｇ当たり以下の組成の有機酸を含有するものである請求項１に記載のメタロ－β－ラクタマーゼ阻害剤。
　　クエン酸　　　　　　　　　　０．５～１．２ｇ
　　リンゴ酸　　　　　　　　　　０．０５～０．５ｇ
　　コハク酸　　　　　　　　　　０．０４～０．３ｇ
　　乳酸　　　　　　　　　　　　０．５～６．０ｇ
　　ギ酸　　　　　　　　　　　　０．０１～０．１ｇ
　　ピルビン酸　　　　　　　　　０．００５～０．０５ｇ
　　遊離γ－アミノ酪酸　　　　　０．０１～０．０５ｇ The metallo-β-lactamase inhibitor according to claim 1, wherein the plant fermentation product contains organic acids having the following composition per 100 g of the plant fermentation product:
Citric acid: 0.5 to 1.2 g
Malic acid 0.05-0.5g
Succinic acid 0.04-0.3g
Lactic acid 0.5-6.0g
Formic acid 0.01-0.1 g
Pyruvic acid 0.005-0.05g
Free γ-aminobutyric acid 0.01-0.05g 　乳酸菌が、ぺディオコッカス・アシディラクティ（P.acidilacti）、ラクトバチルス・ブレビス（L. brevis）、ロイコノストック・メセンテロイデス（L. mesenteroides）、ラクトバチルス・プランタラム（L. plantarum）、ラクトコッカス・ラクチス（L. lactis）、ラクトバチルス・サケイ（L. sakei）、ペディオコッカス・ペントサセウス（P. pentosaceus）、ラクトバチルス・カゼイ（L. casei）およびラクトバチルス・クルバタス（L. curvatus）よりなる群から選ばれた１種または２種以上である請求項１に記載のメタロ－β－ラクタマーゼ阻害剤。 The metallo-β-lactamase inhibitor according to claim 1, wherein the lactic acid bacteria is one or more selected from the group consisting of Pediococcus acidilacti (P. acidilacti), Lactobacillus brevis (L. brevis), Leuconostoc mesenteroides (L. mesenteroides), Lactobacillus plantarum (L. plantarum), Lactococcus lactis (L. lactis), Lactobacillus sakei (L. sakei), Pediococcus pentosaceus (P. pentosaceus), Lactobacillus casei (L. casei) and Lactobacillus curvatus (L. curvatus). 　酵母が、サッカロマイセス・セレビシエ（S. cervisiae）および／又はジゴサッカロマイセス・ロキシー（Z. rouxii）である請求項１に記載のメタロ－β－ラクタマーゼ阻害剤。 The metallo-β-lactamase inhibitor according to claim 1, wherein the yeast is Saccharomyces cerevisiae (S. cervisiae) and/or Zygosaccharomyces rouxii (Z. rouxii). 　請求項１～５の何れか１項に記載のメタロ－β－ラクタマーゼ阻害剤を含有する抗多剤耐性グラム陰性菌用食品。 An anti-multidrug resistant gram-negative bacteria food containing the metallo-β-lactamase inhibitor according to any one of claims 1 to 5. 　請求項１～５の何れか１項に記載のメタロ－β－ラクタマーゼ阻害剤と、抗菌薬とを含有する抗多剤耐性グラム陰性菌用組成物。 An anti-multidrug resistant Gram-negative bacteria composition comprising the metallo-β-lactamase inhibitor according to any one of claims 1 to 5 and an antibacterial agent. 　多剤耐性グラム陰性菌に、抗菌薬と、請求項１～５の何れか１項に記載のメタロ－β－ラクタマーゼ阻害剤を投与することを特徴とする多剤耐性グラム陰性菌の制御方法。 A method for controlling multidrug-resistant gram-negative bacteria, comprising administering to the multidrug-resistant gram-negative bacteria an antibacterial agent and a metallo-β-lactamase inhibitor according to any one of claims 1 to 5. 　多剤耐性グラム陰性菌関連疾患の動物に、抗菌薬と、請求項１～５の何れか１項に記載のメタロ－β－ラクタマーゼ阻害剤を投与することを特徴とする多剤耐性グラム陰性菌関連疾患の治療方法。 A method for treating a multidrug-resistant gram-negative bacteria-associated disease, comprising administering an antibacterial agent and a metallo-β-lactamase inhibitor according to any one of claims 1 to 5 to an animal suffering from a multidrug-resistant gram-negative bacteria-associated disease.
PCT/JP2022/045833 2022-12-13 2022-12-13 METALLO-β-LACTAMASE INHIBITOR AND USE THEREOF Ceased WO2024127496A1 (en)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2009046404A (en) * 2007-08-15 2009-03-05 Kitasato Institute Novel KB-3346-5 substance and production method thereof
WO2022003749A1 (en) * 2020-06-29 2022-01-06 株式会社日本自然発酵 Quality-of-life improving agent

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2009046404A (en) * 2007-08-15 2009-03-05 Kitasato Institute Novel KB-3346-5 substance and production method thereof
WO2022003749A1 (en) * 2020-06-29 2022-01-06 株式会社日本自然発酵 Quality-of-life improving agent

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
TILAHUN MIHRET, KASSA YESHIMEBET, GEDEFIE ALEMU, BELETE MELAKU ASHAGRIE: "Emerging Carbapenem-Resistant Enterobacteriaceae Infection, Its Epidemiology and Novel Treatment Options: A Review", INFECTION AND DRUG RESISTANCE, vol. 14, 21 October 2021 (2021-10-21), pages 4363 - 4374, XP093180982, ISSN: 1178-6973, DOI: 10.2147/IDR.S337611 *
YAN HONG QIONG, HUANG XIAO BO, KE SHI ZHONG, JIANG YI NA, ZHANG YUE HUA, WANG YI NAN, LI JUAN, GAO FENG GUANG: "Interleukin 6 augments lung cancer chemotherapeutic resistance via ataxia-telangiectasia mutated-NF-kappaB pathway activation", CANCER SCIENCE, JAPANESE CANCER ASSOCIATION, TOKYO, JP, vol. 105, no. 9, 1 September 2014 (2014-09-01), JP , pages 1220 - 1227, XP093180981, ISSN: 1347-9032, DOI: 10.1111/cas.12478 *

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