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TW202423405A - Metallo-[beta]-lactamase inhibitor and use thereof - Google Patents

Metallo-[beta]-lactamase inhibitor and use thereof Download PDF

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Publication number
TW202423405A
TW202423405A TW112104841A TW112104841A TW202423405A TW 202423405 A TW202423405 A TW 202423405A TW 112104841 A TW112104841 A TW 112104841A TW 112104841 A TW112104841 A TW 112104841A TW 202423405 A TW202423405 A TW 202423405A
Authority
TW
Taiwan
Prior art keywords
yeast
lactic acid
metallo
lactamase inhibitor
negative bacteria
Prior art date
Application number
TW112104841A
Other languages
Chinese (zh)
Inventor
徳野治
中西雅寛
Original Assignee
日商日本自然發酵股份有限公司
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Filing date
Publication date
Application filed by 日商日本自然發酵股份有限公司 filed Critical 日商日本自然發酵股份有限公司
Publication of TW202423405A publication Critical patent/TW202423405A/en

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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
    • 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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    • 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
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    • A23L19/10—Products from fruits or vegetables; Preparation or treatment thereof of tuberous or like starch containing root crops
    • A—HUMAN NECESSITIES
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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-[beta]-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

金屬－β－內醯胺酶抑制劑及其利用Metallo-β-lactamase inhibitors and their use

本發明係有關於一種金屬-β-內醯胺酶抑制劑及其利用。The present invention relates to a metallo-β-lactamase inhibitor and its use.

現有的抗菌藥對於多重抗藥性革蘭氏陰性菌所引發的感染症幾乎無效，而成為全球性的嚴重問題。Existing antimicrobial drugs are almost ineffective against infections caused by multidrug-resistant Gram-negative bacteria, which has become a serious problem worldwide.

尤其是，向來用作多重抗藥性菌感染症之強效治療藥的碳青黴烯系抗菌藥會被金屬-β-內醯胺酶分解(非專利文獻1)，而有無法治療多重抗藥性革蘭氏陰性菌所引起之感染症的問題。 [先前技術文獻] [專利文獻] In particular, carbapenem antibiotics, which have been used as potent treatments for multidrug-resistant bacterial infections, are degraded by metallo-β-lactamase (non-patent document 1), and there is a problem that they are unable to treat infections caused by multidrug-resistant Gram-negative bacteria. [Prior Art Document] [Patent Document]

[專利文獻1] 國際公開手冊WO2016/093104 [專利文獻2] 國際公開手冊WO2019/009437 [專利文獻3] 國際公開手冊WO2019/009438 [專利文獻4] 國際公開手冊WO2022/003749 [非專利文獻] [Patent Document 1] International Publication Manual WO2016/093104 [Patent Document 2] International Publication Manual WO2019/009437 [Patent Document 3] International Publication Manual WO2019/009438 [Patent Document 4] International Publication Manual WO2022/003749 [Non-Patent Document]

[非專利文獻1] M Tilahun et al. Emerging Carbapenem-Resistant Enterobacteriaceae Infection, Its Epidemiology and Novel Treatment Options: A Review Infectin and Drug Resistance 2021 Oct 21;14:4363-4374. [Non-patent document 1] M Tilahun et al. Emerging Carbapenem-Resistant Enterobacteriaceae Infection, Its Epidemiology and Novel Treatment Options: A Review Infectin and Drug Resistance 2021 Oct 21;14:4363-4374.

[發明所欲解決之課題][The problem that the invention wants to solve]

從而，本發明係以獲取抑制多重抗藥性革蘭氏陰性菌之抗藥性機制而使現有的抗菌藥發揮效果之物質為課題。 [解決課題之手段] Therefore, the present invention aims to obtain a substance that inhibits the drug resistance mechanism of multi-drug resistant Gram-negative bacteria and enables existing antibacterial drugs to exert their effects. [Means for solving the problem]

本案發明人等為解決上述課題而致力研究的結果發現，本案發明人等迄此所開發之闡明老化抑制作用(專利文獻1)、自然致癌預防作用(專利文獻2)、免疫檢查點抑制作用(專利文獻3)、QOL(生活品質)改善作用(專利文獻4)的植物發酵物可抑制多重抗藥性革蘭氏陰性菌的抗藥性機制，使現有的抗菌藥能夠發揮效果，而完成本發明。As a result of the research conducted by the inventors of this case to solve the above-mentioned problems, they found that the plant ferments developed by the inventors of this case so far, which have shown aging inhibition effects (Patent Document 1), natural carcinogenesis prevention effects (Patent Document 2), immune checkpoint inhibition effects (Patent Document 3), and QOL (quality of life) improvement effects (Patent Document 4), can inhibit the drug resistance mechanism of multi-drug resistant Gram-negative bacteria, allowing existing antibacterial drugs to exert their effects, and thus completed the present invention.

亦即，本發明為一種金屬-β-內醯胺酶抑制劑，其係含有下列(a)~(g)的混合物之植物發酵物作為有效成分： (a)大麥、黑豆、紅米、黑米、紅豆、薏苡、稗子、小米及黍所構成之豆・穀物類麴菌發酵物 (b)柑橘、葡萄、蘋果、紫葛、桃子、柿子、木瓜、梨子、西瓜、梅子、無花果、光皮木瓜、南瓜、金橘、柚子、枇杷、杏、大棗、板栗、木天蓼及李子所構成之果實類之酵母及/或乳酸菌發酵物 (c)紫薯、菊芋、胡蘿蔔、洋蔥、甘薯、芋頭、日本山藥、蘿蔔、紅蕪菁、牛蒡、蓮藕、菊薯、百合根、慈姑、生薑、大蒜及薑黃所構成之根菜類・薯類之酵母及/或乳酸菌發酵物 (d)高麗菜、紫蘇、桑葉、魚腥草、艾蒿、山白竹及蒲公英所構成之花・葉菜類之酵母及/或乳酸菌發酵物 (e)昆布、海帶芽及海蘊所構成之海藻類之酵母及/或乳酸菌發酵物 (f)黑芝麻、胡桃及銀杏所構成之種子類之酵母及/或乳酸菌發酵物 (g)舞菇及香菇所構成之菇類之酵母及/或乳酸菌發酵物。 That is, the present invention is a metallo-β-lactamase inhibitor, which contains a plant fermentation product of a mixture of the following (a) to (g) as an active ingredient: (a) bean and cereal fermentation products composed of barley, black beans, red rice, black rice, red beans, coix, barley, millet and sorghum (b) fruit fermentation products composed of citrus, grapes, apples, purple kudzu, peaches, persimmons, papayas, pears, watermelons, plums, figs, smooth papayas, pumpkins, kumquats, grapefruits, loquats, apricots, dates, chestnuts, Polygonum multiflorum and plums (c) Yeast and/or lactic acid bacteria fermentation products of root vegetables and tubers including purple sweet potato, Jerusalem artichoke, carrot, onion, sweet potato, taro, Japanese yam, radish, red turnip, burdock, lotus root, Jerusalem artichoke, lily root, arrowhead, ginger, garlic and turmeric (d) Yeast and/or lactic acid bacteria fermentation products of flower and leaf vegetables including cabbage, perilla, mulberry leaf, houttuynia cordata, mugwort, mountain bamboo and dandelion (e) Yeast and/or lactic acid bacteria fermentation products of seaweed including kelp, kelp sprout and seaweed (f) Yeast and/or lactic acid bacteria fermentation products of seeds including black sesame, walnut and ginkgo (g) Yeast and/or lactic acid bacteria fermentation products of mushrooms including maitake and shiitake.

又，本發明為一種抗多重抗藥性革蘭氏陰性菌用食品，其係含有上述金屬-β-內醯胺酶抑制劑。Furthermore, the present invention is a food for use against multi-drug resistant Gram-negative bacteria, which contains the above-mentioned metal-β-lactamase inhibitor.

再者，本發明為一種抗多重抗藥性革蘭氏陰性菌用組成物，其係含有上述金屬-β-內醯胺酶抑制劑與抗菌藥。Furthermore, the present invention is a composition for use against multi-drug resistant Gram-negative bacteria, which contains the above-mentioned metal-β-lactamase inhibitor and an antibacterial drug.

再者，本發明為一種多重抗藥性革蘭氏陰性菌之控制方法，其特徵為對多重抗藥性革蘭氏陰性菌投予抗菌藥與上述金屬-β-內醯胺酶抑制劑。Furthermore, the present invention is a method for controlling multi-drug resistant Gram-negative bacteria, characterized in that an antibiotic and the above-mentioned metal-β-lactamase inhibitor are administered to the multi-drug resistant Gram-negative bacteria.

更且，本發明為一種多重抗藥性革蘭氏陰性菌相關疾病之治療方法，其特徵為對患有多重抗藥性革蘭氏陰性菌相關疾病之動物投予抗菌藥與上述金屬-β-內醯胺酶抑制劑。 [發明之效果] Furthermore, the present invention is a method for treating diseases associated with multidrug-resistant Gram-negative bacteria, characterized in that an antibacterial drug and the above-mentioned metallo-β-lactamase inhibitor are administered to an animal suffering from a disease associated with multidrug-resistant Gram-negative bacteria. [Effect of the invention]

本發明之金屬-β-內醯胺酶抑制劑由於係以迄此食用經驗豐富的特定植物發酵物作為有效成分，而能夠安全地使用於多重抗藥性革蘭氏陰性菌的控制或治療等地處理、抗多重抗藥性革蘭氏陰性菌用食品等用途。Since the metallo-β-lactamase inhibitor of the present invention uses a specific plant fermentation product with rich edible experience as an active ingredient, it can be safely used in the control or treatment of multi-drug resistant Gram-negative bacteria, food for multi-drug resistant Gram-negative bacteria, etc.

尤其是本發明之金屬-β-內醯胺酶抑制劑係適用於治療感染症等多重抗藥性革蘭氏陰性菌相關疾病。In particular, the metallo-β-lactamase inhibitor of the present invention is suitable for treating multi-drug resistant Gram-negative bacteria-related diseases such as infections.

[實施發明之形態][Form of implementing the invention]

本發明之金屬-β-內醯胺酶抑制劑係含有下述植物發酵物作為有效成分。此植物發酵物為以下(a)~(g)之植物發酵物的混合物。The metallo-β-lactamase inhibitor of the present invention contains the following plant fermentation product as an active ingredient. The plant fermentation product is a mixture of the following plant fermentation products (a) to (g).

(a)使麴菌作用於大麥、黑豆、紅米、黑米、紅豆、薏仁、稗子、小米及黍所構成之豆・穀類而得之發酵物(a) Fermented products obtained by allowing koji to act on beans and grains such as barley, black beans, red rice, black rice, red beans, coix seeds, barnyard grass, millet and sorghum

(b)使酵母及/或乳酸菌作用於柑橘、葡萄、蘋果、野葡萄、桃子、柿子、木瓜、梨子、西瓜、梅子、無花果、光皮木瓜、南瓜、金橘、柚子、枇杷、杏、大棗、板栗、獼猴桃及李子所構成之果實類而得之發酵物，較佳為使酵母作用於前述果實類而得之發酵物(b) fermented products obtained by allowing yeast and/or lactic acid bacteria to act on fruits consisting of citrus, grapes, apples, wild grapes, peaches, persimmons, papayas, pears, watermelons, plums, figs, light-skinned papayas, pumpkins, kumquats, grapefruits, loquats, apricots, dates, chestnuts, kiwis and plums, preferably fermented products obtained by allowing yeast to act on the above fruits

(c)使酵母及/或乳酸菌作用於紫薯、菊芋、胡蘿蔔、洋蔥、甘薯、芋頭、日本山藥、蘿蔔、紅蕪菁、牛蒡、蓮藕、菊薯、百合根、馬蹄蓮、生薑、大蒜及薑黃所構成之根菜類・塊根類而得之發酵物，較佳為使乳酸菌作用於前述根菜類・塊根類而得之發酵物(c) fermented products obtained by allowing yeast and/or lactic acid bacteria to act on root vegetables and tubers consisting of purple sweet potato, Jerusalem artichoke, carrot, onion, sweet potato, taro, Japanese yam, radish, red turnip, burdock, lotus root, Jerusalem artichoke, lily root, water chestnut, ginger, garlic and turmeric, preferably fermented products obtained by allowing lactic acid bacteria to act on the above-mentioned root vegetables and tubers

(d)使酵母及/或乳酸菌作用於高麗菜、紫蘇、桑葉、魚腥草、艾蒿、山白竹及蒲公英所構成之花・葉菜類而得之發酵物，較佳為使乳酸菌作用於前述花・葉菜類而得之發酵物(d) A fermented product obtained by allowing yeast and/or lactic acid bacteria to act on flower and leaf vegetables consisting of cabbage, perilla, mulberry leaf, houttuynia cordata, mugwort, white bamboo and dandelion, preferably a fermented product obtained by allowing lactic acid bacteria to act on the above-mentioned flower and leaf vegetables

(e)使酵母及/或乳酸菌作用於昆布、海帶芽及海蘊所構成之海藻類而得之發酵物，較佳為使酵母作用於前述海藻類而得之發酵物(e) A fermented product obtained by allowing yeast and/or lactic acid bacteria to act on seaweeds consisting of kelp, kelp sprouts and seaweed, preferably a fermented product obtained by allowing yeast to act on the above seaweeds

(f)使酵母及/或乳酸菌作用於黑芝麻、胡桃及銀杏所構成之種子類而得之發酵物，較佳為使酵母作用於前述種子類而得之發酵物(f) a fermented product obtained by allowing yeast and/or lactic acid bacteria to act on seeds consisting of black sesame, walnut and ginkgo, preferably a fermented product obtained by allowing yeast to act on the above seeds

(g)使酵母及/或乳酸菌作用於舞菇及香菇所構成之菇類而得之發酵物，較佳為使乳酸菌作用於前述菇類而得之發酵物(g) A fermented product obtained by allowing yeast and/or lactic acid bacteria to act on mushrooms consisting of Maitake and Shiitake, preferably a fermented product obtained by allowing lactic acid bacteria to act on the aforementioned mushrooms

本發明之金屬-β-內醯胺酶抑制劑能以上述(a)~(g)之發酵物混合而成的植物發酵物直接作為有效成分，惟可進一步藉由使其進行多階段發酵，而提升呈味性或製劑性。The metal-β-lactamase inhibitor of the present invention can directly use the plant fermentation product obtained by mixing the fermentations of (a) to (g) as an active ingredient, but can further enhance the flavor or formulation properties by subjecting it to multi-stage fermentation.

酵母可舉出屬酵母菌屬、接合酵母菌屬等之酵母，其中宜使用釀酒酵母(S. cervisiae)、魯氏接合酵母(Z. rouxii)、甜菜酵母(S. exiguus)等。乳酸菌可舉出例如屬片球菌(Pediococcus)屬、明串珠菌(Leuconostoc)屬、乳桿菌(Lactobacillus)屬、乳球菌(Lactococcus)屬等之乳酸菌，其中宜使用乳酸片球菌(P. acidilacti)、短乳酸菌(L. brevis)、腸膜明串珠菌(L. mesenteroides)、植物乳桿菌(L. plantarum)、乳酸乳球菌(L. lactis)、酒乳桿菌(L. sakei)、戊糖片球菌(P. pentosaceus)、乾酪乳桿菌(L. casei)、羅伊氏乳桿菌(L. reuteri)及彎曲乳桿菌(L. curvatus)等，可使用此等的1種或2種以上。麴菌可例示米麴菌(Aspergillus oryzae)、黑麴菌(Aspergillus niger)、白麴菌(Aspergillus kawachii)等，可使用此等的1種或2種以上。此等酵母、乳酸菌、麴菌可使用市售品、自委託機構等取得者等。Examples of yeast include yeasts belonging to the genus Saccharomyces and the genus Zygosaccharomyces. Among them, brewing yeast (S. cervisiae), Zygosaccharomyces rouxii, beet yeast (S. exiguus), etc. are preferably used. Examples of lactic acid bacteria include lactic acid bacteria belonging to the genus Pediococcus, the genus Leuconostoc, the genus Lactobacillus, and the genus Lactococcus. Among them, P. acidilacti, L. brevis, L. mesenteroides, L. plantarum, L. lactis, L. sakei, P. pentosaceus, L. casei, L. reuteri, and L. curvatus are preferably used. One or more of these may be used. Examples of koji molds 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 a consignment agency.

供予發酵之豆類/穀類、果實等植物可直接使用，或者可視需求進行粉碎、乾燥等前處理。又，亦可視需求添加水而予以稀釋。The beans/grains, fruits and other plants to be fermented can be used directly, or can be pre-treated by crushing, drying and the like as needed. In addition, water can be added to dilute it as needed.

上述(a)~(g)之發酵物可藉由對作為原料之植物接種乳酸菌、酵母或麴菌並進行培養而得。培養只要藉由常用方法來進行即可；例如只要對1種或2種以上之植物的混合物添加約0.001~1質量%的乳酸菌、酵母或麴菌，並以20~50℃進行發酵處理約70~140小時即可。The fermented products of (a) to (g) above can be obtained by inoculating lactic acid bacteria, yeast or koji into plants as raw materials and culturing them. The culturing can be carried out by common methods; for example, about 0.001 to 1% by mass of lactic acid bacteria, yeast or koji is added to a mixture of one or more plants and fermented at 20 to 50°C for about 70 to 140 hours.

亦可將如此所得之(a)~(g)之發酵物混合而直接作為有效成分，惟較佳視需求進一步以20~40℃培養約200~300小時。甚而，較佳使此混合物進行後發酵(熟成)。就後發酵，可視需求使酢酸菌作用，例如，只要添加酢酸發酵物即可；該酢酸發酵物係使上述酵母作用於上述(a)~(g)所包含之植物中的1種或2種以上後，使醋酸桿菌(A.aceti)等醋酸菌與其作用而得。後發酵只要以25~35℃進行70小時~約1年左右即可。經過後發酵之熟成過程，可改善呈味性或製劑性，並可增大抗氧化活性。The fermented products (a) to (g) thus obtained can also be mixed and used directly as an effective ingredient, but it is better to further culture at 20 to 40°C for about 200 to 300 hours as needed. It is even better to subject the mixture to post-fermentation (ripening). For post-fermentation, acetic acid bacteria can be allowed to act as needed. For example, acetic acid fermented products can be added; the acetic acid fermented products are obtained by allowing the above-mentioned yeast to act on one or more of the plants included in the above-mentioned (a) to (g), and then allowing acetic acid bacteria such as Acetobacter (A.aceti) to act on them. Post-fermentation can be carried out at 25 to 35°C for 70 hours to about 1 year. After the aging process of post-fermentation, the taste or preparation properties can be improved, and the antioxidant activity can be increased.

作為用於製造上述植物發酵物之較佳方法的實例，可舉出多段階複合發酵方式。此方法係將以果實類、蔬菜類、海藻類為主原料的複合乳酸菌發酵物與以蔬菜類、根菜類、種子類、菇類、果實類為主要原料的酵母發酵物混合，對其添加以穀類、豆類為主原料的麴菌發酵物，並進一步添加酢酸發酵物予以混合後，進行過濾濃縮，再進行約1年左右的後發酵而成者。藉由此種多階段複合發酵，各發酵生產物進一步由他種菌類合成代謝・轉換，研判可提升風味，同時可提高抗氧化活性等效果。As an example of a preferred method for producing the above-mentioned plant fermented products, a multi-stage complex fermentation method can be cited. This method is to mix a complex lactic acid bacteria fermented product with fruits, vegetables, and seaweed as the main raw materials with a yeast fermented product with vegetables, root vegetables, seeds, mushrooms, and fruits as the main raw materials, add a koji fermented product with cereals and beans as the main raw materials, and further add an acetic acid fermented product to mix, filter and concentrate, and then perform post-fermentation for about 1 year. Through this multi-stage complex fermentation, each fermented product is further synthesized, metabolized, and converted by other bacteria, and it is considered that the flavor can be enhanced and the antioxidant activity can be improved at the same time.

用於本發明之金屬-β-內醯胺酶抑制劑之有效成分的植物發酵物係具有下述(1)至(4)之性質。 (1)呈味性 除源自果物、蔬菜等原料之甜味或有機酸外亦具有源自麴之甜味。雖含有源自原料之多酚類，但苦味較少。 (2)對水溶解性 對水容易溶解。 (3)穩定性 對熱、酸呈穩定，糊膏在室溫保存1年亦無腐敗或呈味性不變。 (4)安全性 用於原料之蔬菜、果物、草本植物等係日常食物，且用於發酵之酵母、乳酸菌、麴菌由於均使用源自食品的釀造或醃漬物等之菌種，故食用經驗豐富。 The plant fermentation used as the active ingredient of the metallo-β-lactamase inhibitor of the present invention has the following properties (1) to (4). (1) Taste In addition to the sweetness or organic acid derived from the raw materials such as fruits and vegetables, it also has the sweetness derived from the koji. Although it contains polyphenols derived from the raw materials, it has less bitterness. (2) Solubility in water It is easily soluble in water. (3) Stability It is stable to heat and acid, and the paste does not spoil or change in taste even if it is stored at room temperature for 1 year. (4) Safety The raw materials such as vegetables, fruits, and herbs are daily foods, and the yeast, lactic acid bacteria, and koji used for fermentation are all strains derived from food brewing or pickling, so they have rich edible experience.

本發明所使用之植物發酵物係具有下述(a)~(d)之性質。The plant fermentation products used in the present invention have the following properties (a) to (d).

(a)一般成分(每100g) 　　水分 15~35g 　　蛋白質 5~20g 　　脂質 1~8g 　　灰分 1~5g 　　碳水化合物 30~70g 　　鈉 40~150mg 　　維生素B6 0.1~0.5mg 　　熱量 200~500kcal (a) General ingredients (per 100g) Moisture 15~35g Protein 5~20g Lipids 1~8g Ash 1~5g carbohydrate 30~70g Sodium 40~150mg Vitamin B6 0.1~0.5mg Calories 200~500kcal

(b)胺基酸組成(每100g) 　　精胺酸 0.2~0.6g 　　離胺酸 0.1~0.7g 　　組胺酸 0.1~0.4g 　　苯丙胺酸 0.2~0.8g 　　酪胺酸 0.1~0.6g 　　白胺酸 0.3~1.2g 　　異白胺酸 0.2~0.8g 　　甲硫胺酸 0.05~0.3g 　　纈胺酸 0.2~0.9g 　　丙胺酸 0.2~0.9g 　　甘胺酸 0.2~0.7g 　　脯胺酸 0.4~1.2g 　　麩胺酸 1.2~3.0g 　　絲胺酸 0.2~0.8g 　　蘇胺酸 0.2~0.7g 　　天門冬胺酸 0.4~1.5g 　　色胺酸 0.03~0.15g 　　半胱胺酸 0.05~0.40g (b) Amino acid composition (per 100g) 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 Glutamine 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 Cysteine 0.05~0.40g

(c)有機酸組成(每100g) 　　檸檬酸 0.5~1.2g 　　蘋果酸 0.05~0.5g 　　琥珀酸 0.04~0.3g 　　乳酸 0.5~6.0g 　　甲酸 0.01~0.1g 　　丙酮酸 0.005~0.05g 　　游離γ-胺基丁酸 0.01~0.05g (c) Organic acid composition (per 100g) Citric Acid 0.5~1.2g Apple acid 0.05~0.5g Succinic acid 0.04~0.3g Lactic acid 0.5~6.0g Formic acid 0.01~0.1g Pyruvate 0.005~0.05g Free GABA 0.01~0.05g

(d)礦物質組成(每100g) 　　磷 100~400mg 　　鐵 1~5mg 　　鈣 500~900mg 　　鉀 600~1000mg 　　鎂 70~120mg 　　鋅 0.8~1.6mg 　　碘 1.0~2.5mg (d) Mineral composition (per 100g) phosphorus 100~400mg Iron 1~5mg Calcium 500~900mg Potassium 600~1000mg Magnesium 70~120mg Zinc 0.8~1.6mg iodine 1.0~2.5mg

上述植物發酵物由於具有金屬-β-內醯胺酶抑制作用，藉由將其作為有效成分，可作成金屬-β-內醯胺酶抑制劑。植物發酵物可抑制之金屬-β-內醯胺酶不特別限定，可舉出NDM型金屬-β-內醯胺酶、IMP型金屬-β-內醯胺酶等，較佳為有全球性地理擴散以及朝包含各種病原菌之腸內細菌科細菌之異菌種間擴散之疑慮的NDM型金屬-β-內醯胺酶。Since the plant fermentation product has a metallo-β-lactamase inhibitory effect, a metallo-β-lactamase inhibitor can be prepared by using it as an active ingredient. The metallo-β-lactamase that can be inhibited by the plant fermentation product is not particularly limited, and examples thereof include NDM-type metallo-β-lactamase, IMP-type metallo-β-lactamase, etc., preferably NDM-type metallo-β-lactamase, which is suspected of global geographical spread and interspecies spread to enterobacteriaceae bacteria including various pathogens.

以上說明之植物發酵物由於具有金屬-β-內醯胺酶之抑制作用，可作為金屬-β-內醯胺酶抑制劑而利用。此外，植物發酵物是否具有金屬-β-內醯胺酶之抑制作用，能以實施例所記載之試驗來確認。又，上述植物發酵物之金屬-β-內醯胺酶之抑制作用，以蛋白質量計約為20μg以上，較佳為30~60μg時與抗菌藥數μg顯示相乘效果。The plant fermented product described above can be used as a metallo-β-lactamase inhibitor because it has a metallo-β-lactamase inhibitory effect. In addition, whether the plant fermented product has a metallo-β-lactamase inhibitory effect can be confirmed by the test described in the examples. In addition, the metallo-β-lactamase inhibitory effect of the plant fermented product shows a synergistic effect with several μg of the antibacterial drug when the protein mass is about 20 μg or more, preferably 30-60 μg.

本發明之金屬-β-內醯胺酶抑制劑可直接使用上述植物發酵物，或者亦可依循週知之製劑學製法，添加藥理學上可容許之載體、賦形劑、水分活性調整劑等而製劑化。植物發酵物可視需求經濃縮而調整濃度，或藉由噴霧或冷凍乾燥等而粉末化。作為製劑化時使用之載體或賦形劑，可使用例如乳糖、葡萄糖、蔗糖、澱粉、糖類混合物等。最終形態可舉出溶液、膏劑、軟膠囊、嚼錠劑、膠囊、散劑、顆粒劑、糖漿劑、口服液、噴霧劑、軟膏、乳膏劑、外用液劑、滴眼劑、滴鼻劑、栓劑、貼劑等。就其用量、用法，例如以有效成分之植物發酵物計，只要按成人每日0.1g以上，較佳為0.1~12g，更佳為0.6~10g(以固體成分換算)左右口服攝取即可。作為將此種植物發酵物製劑化而製成食品形態之市售品，可舉出天生酵素金印、天生酵素膠囊、Amo-Koso(皆為日本自然發酵公司製)等。The metallo-β-lactamase inhibitor of the present invention can be directly used as the above-mentioned plant fermentation, or can be formulated according to the known pharmaceutical preparation method by adding pharmacologically acceptable carriers, excipients, water activity regulators, etc. The plant fermentation can be concentrated to adjust the concentration as required, or powdered by spraying or freeze drying. For example, lactose, glucose, sucrose, starch, sugar mixtures, etc. can be used as carriers or excipients used in the formulation. The final form can be solution, paste, soft capsule, chewable tablet, capsule, powder, granule, syrup, oral solution, spray, ointment, cream, external liquid, eye drops, nasal drops, suppository, patch, etc. In terms of dosage and usage, for example, based on the active ingredient of plant fermentation, it only needs to be taken orally at a daily dose of 0.1g or more, preferably 0.1-12g, and more preferably 0.6-10g (converted to solid content) for adults. Examples of commercial products that are food products made by converting plant fermentation products into food preparations include Natural Enzyme Kinsei, Natural Enzyme Capsules, and Amo-Koso (all manufactured by Japan Natural Fermentation Co., Ltd.).

本發明之金屬-β-內醯胺酶抑制劑可藉由對患有多重抗藥性革蘭氏陰性菌相關疾病之動物，較佳為患有多重抗藥性革蘭氏陰性菌相關疾病之人類以外的動物，與抗菌藥共同投予，而治療多重抗藥性革蘭氏陰性菌相關疾病。作為多重抗藥性革蘭氏陰性菌相關疾病，不特別限定，例如命危之重病可舉出肺炎或敗血症等疾病。又，抗菌藥不特別限定，可舉出例如芐青黴素鉀(PCG)、噁唑西林鈉(MPIPC)、氨芐西林鈉(ABPC)、阿莫西林(AMPC)、哌拉西林鈉(PIPC)、甲苯磺酸舒他黴素(SBTPC)等青黴素系抗菌藥、頭孢噻吩鈉(CET)、頭孢唑啉鈉(CEZ)、頭孢替安鹽酸鹽(CTM)、頭孢哌酮鈉(CPZ)、頭孢噻肟鈉(CTX)、頭孢唑肟鈉(CZX)、頭孢甲肟鹽酸鹽(CMX)、頭孢他啶(CAZ)、頭孢曲松鈉(CTRX)、頭孢匹羅硫酸鹽(CPR)、頭孢吡肟鹽酸鹽(CFPM)、頭孢唑侖鹽酸鹽(CZOP)、頭孢氨芐(CEX)、頭孢克洛(CCL)、頭孢沙嗪(CXD)、頭孢克肟(CFIX)、頭孢丁烯(CETB)、頭孢地尼(CFDN)、頭孢呋辛鈉(CXM)、頭孢泊肟鈉(CPDX)、頭孢特崙鹽酸鹽(CFTM)、頭孢卡平鈉(CFPN)、頭孢托崙鈉(CDTR)等頭孢類抗菌藥、亞胺培南(IPM)、美羅培南三水合物(MEPM)、比阿培南(BIPM)、多尼培南水合物(DRPM)、替比培南水合物(TBPM)等碳青黴烯系抗菌藥等。The metallo-β-lactamase inhibitor of the present invention can be administered together with an antibacterial drug to an animal suffering from a multidrug-resistant Gram-negative bacteria-related disease, preferably an animal other than a human suffering from a multidrug-resistant Gram-negative bacteria-related disease, to treat a multidrug-resistant Gram-negative bacteria-related disease. The multidrug-resistant Gram-negative bacteria-related disease is not particularly limited, and for example, a life-threatening serious disease may include pneumonia or sepsis. In addition, the antibacterial drug is not particularly limited, and examples thereof include penicillin potassium (PCG), oxacillin sodium (MPIPC), ampicillin sodium (ABPC), amoxicillin (AMPC), piperacillin sodium (PIPC), sultamicin tosylate (SBTPC) and other penicillin-based antibacterial drugs, ceftriaxone sodium (CET), cefazolin sodium (CEZ), cefotiam hydrochloride (CTM), cefoperazone sodium (CPZ), ceftriaxone sodium (CTX), cefazolin sodium (CZX), cefmenoxime hydrochloride (CMX), ceftazidime (CAZ), ceftriaxone sodium (CTRX), cefpirome sulfate (CPR), cefepime hydrochloride (CTM), and cefoperazone sodium (CPZ). Cephalosporin antibiotics such as cefuroxime (CFP), cefazolin (CZOP), cefuroxime (CEX), cefaclor (CCL), cefotaxime (CXD), cefuroxime (CFIX), cefbutromycin (CETB), cefdinir (CFDN), cefuroxime sodium (CXM), cefpodoxime sodium (CPDX), cefterone hydrochloride (CFTM), cefcarpine sodium (CFPN), cefditoren sodium (CDTR), and carbapenem antibiotics such as imipenem (IPM), meropenem trihydrate (MEPM), biapenem (BIPM), doripenem hydrate (DRPM), and tebipenem hydrate (TBPM).

對患有多重抗藥性革蘭氏陰性菌相關疾病之動物投予本發明之金屬-β-內醯胺酶抑制劑的方法不特別限定，可為外用、內服任一種。The method of administering the metallo-β-lactamase inhibitor of the present invention to animals suffering from multidrug-resistant Gram-negative bacteria-related diseases is not particularly limited, and the method may be either external or internal administration.

本發明之金屬-β-內醯胺酶抑制劑可抑制多重抗藥性革蘭氏陰性菌之抗藥性機制，可使現有的抗菌藥發揮效果。因此，藉由對多重抗藥性革蘭氏陰性菌投予抗菌藥與本發明之金屬-β-內醯胺酶抑制劑，可抑制多重抗藥性革蘭氏陰性菌。此處所稱多重抗藥性革蘭氏陰性菌，係指對上述抗菌藥具有抗藥性，無法藉由抗菌藥而抑制其增生的革蘭氏陰性菌。The metal-β-lactamase inhibitor of the present invention can inhibit the drug resistance mechanism of multi-drug resistant Gram-negative bacteria and make the existing antibacterial drugs effective. Therefore, by administering antibacterial drugs and the metal-β-lactamase inhibitor of the present invention to multi-drug resistant Gram-negative bacteria, multi-drug resistant Gram-negative bacteria can be inhibited. The multi-drug resistant Gram-negative bacteria referred to herein refer to Gram-negative bacteria that are resistant to the above-mentioned antibacterial drugs and whose proliferation cannot be inhibited by antibacterial drugs.

要治療上述多重抗藥性革蘭氏陰性菌相關疾病、或控制多重抗藥性革蘭氏陰性菌，亦可利用含有本發明之金屬-β-內醯胺酶抑制劑與上述抗菌藥的抗多重抗藥性革蘭氏陰性菌用組成物。此組成物中之抗菌藥的含量不特別限定，只要是抗菌藥通常可發揮效果的量。To treat the above-mentioned multidrug-resistant Gram-negative bacteria-related diseases or control multidrug-resistant Gram-negative bacteria, a composition for treating multidrug-resistant Gram-negative bacteria containing the metallo-β-lactamase inhibitor of the present invention and the above-mentioned antibacterial drug can also be used. The content of the antibacterial drug in this composition is not particularly limited as long as it is an amount at which the antibacterial drug can normally exert its effect.

上述本發明之抗多重抗藥性革蘭氏陰性菌用組成物可與本發明之金屬-β-內醯胺酶抑制劑同樣地製劑化。作為最終形態，可與本發明之金屬-β-內醯胺酶抑制劑同樣地舉出溶液、膏劑、軟膠囊、嚼錠劑、膠囊、散劑、顆粒劑、糖漿劑、口服液、噴霧劑、軟膏、乳膏劑、外用液劑、滴眼劑、滴鼻劑、栓劑、貼劑等。The composition for use against multidrug-resistant Gram-negative bacteria of the present invention can be formulated in the same manner as the metallo-β-lactamase inhibitor of the present invention. As the final form, it can be in the form of solution, ointment, soft capsule, chewable tablet, capsule, powder, granule, syrup, oral liquid, spray, ointment, cream, external liquid, eye drops, nasal drops, suppository, patch, etc., in the same manner as the metallo-β-lactamase inhibitor of the present invention.

此外，由於本發明之金屬-β-內醯胺酶抑制劑亦為食用經驗長久的食品成分，故可作為抗多重抗藥性革蘭氏陰性菌用食品而利用。就此食品，作為向來週知之食品的原料或調味料的一部分，可僅使用本發明之金屬-β-內醯胺酶抑制劑之有效成分的植物發酵物。具體之食品可舉出例如味噌等調味料、吐司等麵包類、煎餅、餅乾、巧克力、糖果、日式饅頭、蛋糕等甜點類、優格、起司等乳製品、蘿蔔乾等醃漬品類、拉麵、蕎麥麵、烏龍麵等麵類、玉米濃湯、海帶芽湯等湯類、冷飲、健康飲料、碳酸飲料、果汁飲料等。 [實施例] In addition, since the metallo-β-lactamase inhibitor of the present invention is also a food ingredient with a long history of consumption, it can be used as a food for multi-drug resistant Gram-negative bacteria. For this food, as a part of the raw materials or seasonings of conventionally known foods, only plant fermentation, which is the active ingredient of the metallo-β-lactamase inhibitor of the present invention, can be used. Specific foods include condiments such as miso, breads such as toast, desserts such as pancakes, cookies, chocolate, candy, Japanese steamed buns, cakes, dairy products such as yogurt and cheese, pickled foods such as dried radishes, noodles such as ramen, buckwheat noodles, and udon noodles, soups such as corn soup and kelp sprout soup, cold drinks, health drinks, carbonated drinks, fruit juices, etc. [Examples]

以下舉出本發明之實施例詳細說明本發明，惟本發明不受此等實施例任何限定。The present invention is described in detail below with reference to the embodiments of the present invention, but the present invention is not limited to these embodiments in any way.

製造例1 植物發酵物的製造： 使用以下植物作為原料。 (a)豆・穀類(大麥、黑豆、紅米、黑米、紅豆、薏苡、稗子、小米、黍) (b)果實類(柑橘、葡萄、蘋果、紫葛、桃子、柿子、木瓜、梨子、西瓜、梅子、無花果、光皮木瓜、南瓜、金橘、柚子、枇杷、杏、大棗、板栗、木天蓼、李子) (c)根菜類(紫薯、菊芋、胡蘿蔔、洋蔥、甘薯、芋頭、日本山藥、蘿蔔、紅蕪菁、牛蒡、蓮藕、菊薯、百合根、慈姑、生薑、大蒜、薑黃) (d)花・葉菜類(高麗菜、紫蘇、桑葉、魚腥草、艾蒿、山白竹、蒲公英) (e)海草類(昆布、海帶芽、海蘊) (f)種子類(黑芝麻、胡桃、銀杏) (g)菇類(舞菇、香菇) Production Example 1 Production of plant fermentation products: Use the following plants as raw materials. (a) Beans and grains (barley, black beans, red rice, black rice, red beans, coix, barley, millet, sorghum) (b) Fruits (citrus, grapes, apples, purple kudzu, peaches, persimmons, papayas, pears, watermelons, plums, figs, papayas, pumpkins, kumquats, grapefruits, loquats, apricots, dates, chestnuts, safflower, plums) (c) Root vegetables (purple sweet potatoes, Jerusalem artichokes, carrots, onions, sweet potatoes, taro, Japanese yam, radish, red radish, burdock, lotus roots, Jerusalem artichokes, lily roots, arrowheads, ginger, garlic, turmeric) (d) Flowers and leafy vegetables (cabbage, perilla, mulberry leaves, houttuynia cordata, mugwort, mountain white bamboo, dandelions) (e) Seaweed (kelp, kelp sprouts, seaweed) (f) Seeds (black sesame, walnut, ginkgo) (g) Mushrooms (maitake, shiitake)

對上述(c)、(d)及(g)之原料(730g)接種0.2質量%之以乳酸菌類(P. acidilacti, L. brevis, L. mesenteroides, L. plantarum, L. lactis, L. sakei, L. casei)調製成約1.0×10 5cfu/g之菌種濃度的培養液，以30℃進行50小時培養。又，對上述(b)、(e)及(f)之原料(900kg)接種0.4質量%之酵母類(S. cervisiae 5種、Z. rouxii 2種)調製成約1.0×10 5cfu/g之菌種濃度的培養液，以30℃進行50小時培養。對(a)豆類及穀類系原料(1000kg)接種0.1質量%之麴菌類(黃麴菌、黑麴菌、白麴菌)並以35℃進行70小時培養。其次，將各培養物混合後，以30℃進行200小時培養。對完成發酵的醪進行固液分離操作，將所得濾液濃縮而調成糊狀後分注至容器中，進一步發酵(熟成)1年後而得到植物發酵物。 The raw materials (c), (d) and (g) were inoculated with 0.2 mass % of a culture solution prepared with lactic acid bacteria (P. acidilacti, L. brevis, L. mesenteroides, L. plantarum, L. lactis, L. sakei, L. casei) to a bacterial concentration of about 1.0×10 5 cfu/g, and cultured at 30°C for 50 hours. The raw materials (b), (e) and (f) were inoculated with 0.4 mass % of a culture solution prepared with yeast (5 species of S. cervisiae and 2 species of Z. rouxii) to a bacterial concentration of about 1.0×10 5 cfu/g, and cultured at 30°C for 50 hours. (a) Bean and cereal raw materials (1000 kg) were inoculated with 0.1% by mass of koji fungi (yellow Aspergillus, black Aspergillus, white Aspergillus) and cultured at 35°C for 70 hours. Then, the cultures were mixed and cultured at 30°C for 200 hours. The fermented mash was subjected to solid-liquid separation, and the obtained filtrate was concentrated and mixed into a paste and then dispensed into containers. After further fermentation (aging) for 1 year, a plant fermentation product was obtained.

製造例1中所得之植物發酵物係具有以下性質。 (a)一般分析值(每100g) 　　水分 25.2g 　　蛋白質 11.8g 　　脂質 3.6g 　　灰分 2.1g 　　碳水化合物 57.3g 　　鈉 54.0mg 　　維生素B6 0.20mg 　　熱量 309kcal The plant fermentation product obtained in Preparation Example 1 has the following properties. (a) General analytical value (per 100 g) Moisture 25.2g Protein 11.8g Lipids 3.6g Ash 2.1g carbohydrate 57.3g Sodium 54.0mg Vitamin B6 0.20mg Calories 309kcal

(b)胺基酸組成(每100g) 將試料以6N鹽酸水解後藉由胺基酸自動分析計進行分析。就半胱胺酸，係實施過甲酸氧化處理後，使用鹽酸水解。色胺酸係使用高效液相層析法。 　　精胺酸 0.33g 　　離胺酸 0.34g 　　組胺酸 0.22g 　　苯丙胺酸 0.51g 　　酪胺酸 0.32g 　　白胺酸 0.74g 　　異白胺酸 0.42g 　　甲硫胺酸 0.13g 　　纈胺酸 0.54g 　　丙胺酸 0.48g 　　甘胺酸 0.42g 　　脯胺酸 0.92g 　　麩胺酸 2.25g 　　絲胺酸 0.4g 　　蘇胺酸 0.36g 　　天門冬胺酸 0.84g 　　色胺酸 0.06g 　　半胱胺酸 0.15g (b) Amino acid composition (per 100 g) The sample was hydrolyzed with 6N hydrochloric acid and analyzed by an amino acid automatic analyzer. Cysteine was oxidized with performic acid and then hydrolyzed with hydrochloric 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 Glutamine 2.25g Serine 0.4g Threonine 0.36g Aspartic acid 0.84g Tryptophan 0.06g Cysteine 0.15g

(c)有機酸組成(每100g) 　　檸檬酸 0.81g 　　蘋果酸 0.31g 　　琥珀酸 0.12g 　　乳酸 1.17g 　　甲酸 0.03g 　　丙酮酸 0.01g 　　游離γ-胺基丁酸 24mg (c) Organic acid composition (per 100g) Citric Acid 0.81g Apple acid 0.31g Succinic acid 0.12g Lactic acid 1.17g Formic acid 0.03g Pyruvate 0.01g Free GABA 24mg

(d)礦物質組成(每100g) 　　磷 262mg 　　鐵 2.65mg 　　鈣 72.1mg 　　鉀 798mg 　　鎂 97.8mg 　　鋅 1.19mg 　　碘 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

此植物發酵物係與天生酵素金印(日本自然發酵公司製)相同者，在以下實施例中加以使用。This plant ferment is the same as the natural enzyme Kinjiru (manufactured by Japan Natural Fermentation Co., Ltd.) and is used in the following examples.

實施例1 製造例1中調製之植物發酵物的物性： (1)最低抑菌濃度的測定 秤量製造例1中調製之植物發酵物，添加其2倍的滅菌水，滲透一夜後使成分溶出，將離心分離後的上清液以0.22μm的濾紙過濾後作為試料。使用此試料，探討對多重抗藥性革蘭氏陰性菌之MIC。 Example 1 Physical properties of the plant fermented product prepared in Example 1: (1) Determination of minimum inhibitory concentration The plant fermented product prepared in Example 1 was weighed, and twice the amount of sterilized water was added. After permeation overnight, the components were dissolved. The supernatant after centrifugation was filtered through a 0.22 μm filter paper and used as a sample. This sample was used to investigate the MIC against multidrug-resistant Gram-negative bacteria.

由此結果，植物發酵物之對多重抗藥性革蘭氏陰性菌之MIC為1/4濃度。As a result, the MIC of plant ferments against multidrug-resistant Gram-negative bacteria was 1/4 of the concentration.

(2)組合試驗 使用將各種抗菌藥之濃度梯度系列形成固相之藥劑感受性試驗孔盤(乾式孔盤榮研：榮研化學製)與多重抗藥性革蘭氏陰性菌來進行組合試驗。將其結果示於圖2。此外，各孔盤中以0、1/10或1/16添加有植物發酵物(試料)，並添加一定量的多重抗藥性革蘭氏陰性菌。 (2) Combination test A combination test was conducted using a drug sensitivity test plate (Dry Plate Eiken: Eiken Chemical Co., Ltd.) in which a concentration gradient series of various antimicrobial drugs was formed into a solid phase and multidrug-resistant Gram-negative bacteria. The results are shown in Figure 2. In addition, plant fermentation (sample) was added to each plate at 0, 1/10, or 1/16, and a certain amount of multidrug-resistant Gram-negative bacteria was added.

由此結果，僅有抗菌藥時，對多重抗藥性革蘭氏陰性菌未看出其效果；以低於MIC的1/8~1/10添加植物發酵物，就美羅培南或多尼培南等碳青黴烯系，甚或頭孢吡肟等頭孢系抗菌藥，可阻止多重抗藥性革蘭氏陰性菌的增生而使MIC大幅降低。As a result, when only antibiotics are used, no effect is seen against multidrug-resistant Gram-negative bacteria; adding plant ferments at a concentration lower than 1/8~1/10 of the MIC, carbapenems such as meropenem or doripenem, or even cephalosporin antibiotics such as cefepime, can prevent the proliferation of multidrug-resistant Gram-negative bacteria and significantly reduce the MIC.

(3)縱橫交錯試劑 於組合試驗中，係針對再現性相對較高的美羅培南(MEPM)及多尼培南(DRPM)，為確認植物發酵物的併用效果而進行縱橫交錯試驗。縱橫交錯試驗係於96孔孔板中對抗菌藥與植物發酵物賦予濃度梯度而分配，添加多重抗藥性革蘭氏陰性菌培養一夜，於各井孔中算出FIC index而判定併用效果。將縱橫交錯試驗的結果示於圖3。此外，就相乘/相加效果的判定，係根據下述計算式求出FIC index (fractional inhibitory concentration)，將0.5以下判定為“有相乘效果”。 (3) Vertical and horizontal cross-talk test In the combination test, a vertical and horizontal cross-talk test was conducted to confirm the combined effect of plant ferments for meropenem (MEPM) and doripenem (DRPM), which have relatively high reproducibility. In the vertical and horizontal cross-talk test, antibiotics and plant ferments were distributed in a 96-well plate with a concentration gradient, multidrug-resistant Gram-negative bacteria were added and cultured overnight, and the FIC index was calculated in each well to determine the combined effect. The results of the vertical and horizontal cross-talk test are shown in Figure 3. In addition, the FIC index (fractional inhibitory concentration) was calculated according to the following calculation formula to determine the multiplicative/additive effect, and a value below 0.5 was determined as "a multiplicative effect".

[數1] FIC index=(併用時的MIC)/(抗菌藥單獨的MIC)+(併用時的MIC)/(植物發酵物單獨的MIC) [Number 1] FIC index=(MIC when used together)/(MIC of the antibiotic alone)+(MIC when used together)/(MIC of the plant ferment alone)

由此結果，僅有抗菌藥時，對多重抗藥性革蘭氏陰性菌未看出其效果；以1/8~1/10添加植物發酵物，就美羅培南或多尼培南等碳青黴烯系，甚或頭孢吡肟等頭孢系抗菌藥，可阻止多重抗藥性革蘭氏陰性菌的增生而使MIC大幅降低。As a result, when only antibiotics were used, no effect was seen on multidrug-resistant Gram-negative bacteria; adding plant ferments at 1/8~1/10, carbapenems such as meropenem or doripenem, or even cephalosporins such as cefepime, could prevent the proliferation of multidrug-resistant Gram-negative bacteria and significantly reduce MIC.

(4)硝噻吩試驗 為探討金屬-β-內醯胺酶的活性，而依循常用方法(石井良和等人, 「喀痰中β-內醯胺酶活性之測定方法的確立相關探討」, 日本化學療法學會雜誌, Vol.47, No.10，p619-622(1999))進行硝噻吩試驗。由於在植物發酵物(圖中：發酵液)的存在下，因硝噻吩的分解而發出紅色者與陽性對照相比被抑制，因此金屬-β-內醯胺酶的活性降低而使碳青黴烯系等現有的抗菌藥發揮其效力(圖4)。此外，巰機乙酸係指向來週知之試管內的金屬-β-內醯胺酶抑制劑。 (4) Nitrothiophene test In order to investigate the activity of metallo-β-lactamase, the nitrothiophene test was conducted according to the commonly used method (Ishii Yoshikazu et al., "Study on the establishment of a method for determining β-lactamase activity in sputum", Journal of the Japanese Society of Chemical Therapy, Vol.47, No.10, p619-622 (1999)). Since the red color emitted by the decomposition of nitrothiophene in the presence of plant fermentation (fermentation liquid in the figure) is inhibited compared to the positive control, the activity of metallo-β-lactamase is reduced, allowing existing antibacterial drugs such as carbapenems to exert their efficacy (Figure 4). In addition, acetic acid refers to the in vitro metallo-β-lactamase inhibitor known in the past.

實施例2 抗多重抗藥性革蘭氏陰性菌用組成物的調製： 將實施例1中調製之植物發酵物的10g與抗菌藥(美羅培南)0.5g混合，將其用水稀釋後，經調味而調製成液態抗多重抗藥性革蘭氏陰性菌用組成物。 Example 2 Preparation of a composition for fighting multidrug-resistant Gram-negative bacteria: 10 g of the plant fermented product prepared in Example 1 was mixed with 0.5 g of an antibacterial drug (meropenem), diluted with water, and seasoned to prepare a liquid composition for fighting multidrug-resistant Gram-negative bacteria.

實施例3 抗多重抗藥性革蘭氏陰性菌用組成物的調製： 將實施例1中調製之植物發酵物的10g與抗菌藥(美羅培南)0.5g混合，調製成糊狀的抗多重抗藥性革蘭氏陰性菌用組成物。 Example 3 Preparation of a composition for fighting multidrug-resistant Gram-negative bacteria: 10 g of the plant fermented product prepared in Example 1 was mixed with 0.5 g of an antibacterial drug (meropenem) to prepare a paste-like composition for fighting multidrug-resistant Gram-negative bacteria.

實施例4 抗多重抗藥性革蘭氏陰性菌用食品(類味噌食品)： 將製造例1中製造之植物發酵物與味噌混合，用調味料調味而製成抗多重抗藥性革蘭氏陰性菌用食品(類味噌食品)。 Example 4 Food for fighting multidrug-resistant Gram-negative bacteria (miso-like food): The plant fermentation product produced in Production Example 1 is mixed with miso and seasoned with seasoning to prepare food for fighting multidrug-resistant Gram-negative bacteria (miso-like food).

實施例5 抗多重抗藥性革蘭氏陰性菌用食品(飲料)： 將製造例1中製造之植物發酵物溶解於水中後，混合高果糖漿與果汁，經調味而製成抗多重抗藥性革蘭氏陰性菌用食品(飲料)。 Example 5 Food (drink) for fighting multidrug-resistant Gram-negative bacteria: The plant fermentation produced in Production Example 1 is dissolved in water, mixed with high fructose syrup and fruit juice, and seasoned to prepare food (drink) for fighting multidrug-resistant Gram-negative bacteria.

實施例6 抗多重抗藥性革蘭氏陰性菌用食品(軟膠囊)： 將製造例1中製造之植物發酵物與植物油、卵磷脂混合後以常用方法填充於軟膠囊中而製成抗多重抗藥性革蘭氏陰性菌用食品(軟膠囊)。 Example 6 Food (soft capsule) for fighting multidrug-resistant Gram-negative bacteria: The plant fermentation product prepared in Preparation Example 1 is mixed with vegetable oil and lecithin and then filled into soft capsules by a common method to prepare food (soft capsule) for fighting multidrug-resistant Gram-negative bacteria.

實施例7 抗多重抗藥性革蘭氏陰性菌用食品(口嚼錠)： 將製造例1中製造之植物發酵物與結晶纖維素、白糖混合後以常用方法進行打錠而製成用於QOL改善之抗多重抗藥性革蘭氏陰性菌用食品(口嚼錠)。 Example 7 Food for multidrug-resistant Gram-negative bacteria (chewable tablets): The plant fermentation product prepared in Preparation Example 1 is mixed with crystallized cellulose and white sugar and then tableted in a conventional manner to prepare a food for multidrug-resistant Gram-negative bacteria (chewable tablets) for improving QOL.

實施例8 抗多重抗藥性革蘭氏陰性菌用食品(軟膠囊)： 將製造例1中製造之植物發酵物(一天份的量)與植物油、卵磷脂及甲肌肽900mg混合後以常用方法填充於軟膠囊中而製成抗多重抗藥性革蘭氏陰性菌用食品(軟膠囊)。 [產業上可利用性] Example 8 Food (soft capsule) for fighting multidrug-resistant Gram-negative bacteria: The plant fermentation product (amount for one day) produced in Production Example 1 was mixed with vegetable oil, lecithin and 900 mg of carnosine, and then filled into soft capsules by a common method to prepare food (soft capsule) for fighting multidrug-resistant Gram-negative bacteria. [Industrial Applicability]

本發明之金屬-β-內醯胺酶抑制劑由於可抑制多重抗藥性革蘭氏陰性菌之抗藥性機制，而使抗菌藥發揮效果，故可利用於治療多重抗藥性革蘭氏陰性菌相關疾病。The metallo-β-lactamase inhibitor of the present invention can inhibit the drug resistance mechanism of multi-drug resistant Gram-negative bacteria, thereby making the antibacterial drugs effective, and thus can be used to treat diseases related to multi-drug resistant Gram-negative bacteria.

[圖1]為表示實施例1之(1)最小抑菌濃度的測定的圖。 [圖2]為表示實施例1之(2)組合試驗的結果的圖(圖中，左上係植物發酵物為0之孔盤、右上係植物發酵物為1/10之孔盤、左下為顯示抗菌藥的種類與其濃度之資訊、右下係植物發酵物(金印)1/16之孔盤)。 [圖3]為表示實施例1之(3)縱橫交錯試驗的結果的圖。 [圖4]為表示硝噻吩試驗的結果的圖。 [Figure 1] is a graph showing the determination of the minimum inhibitory concentration in Example 1 (1). [Figure 2] is a graph showing the results of the combined test in Example 1 (2) (in the figure, the upper left is a plate with a plant fermentation of 0, the upper right is a plate with a plant fermentation of 1/10, the lower left is information showing the type of antibacterial drug and its concentration, and the lower right is a plate with a plant fermentation (Kinyin) of 1/16). [Figure 3] is a graph showing the results of the vertical and horizontal staggered test in Example 1 (3). [Figure 4] is a graph showing the results of the nitrothiophene test.

Claims (9)

一種金屬-β-內醯胺酶抑制劑，其係含有下列(a)~(g)的混合物之植物發酵物作為有效成分： (a)大麥、黑豆、紅米、黑米、紅豆、薏苡、稗子、小米及黍所構成之豆・穀物類麴菌發酵物 (b)柑橘、葡萄、蘋果、紫葛、桃子、柿子、木瓜、梨子、西瓜、梅子、無花果、光皮木瓜、南瓜、金橘、柚子、枇杷、杏、大棗、板栗、木天蓼及李子所構成之果實類之酵母及/或乳酸菌發酵物 (c)紫薯、菊芋、胡蘿蔔、洋蔥、甘薯、芋頭、日本山藥、蘿蔔、紅蕪菁、牛蒡、蓮藕、菊薯、百合根、慈姑、生薑、大蒜及薑黃所構成之根菜類・薯類之酵母及/或乳酸菌發酵物 (d)高麗菜、紫蘇、桑葉、魚腥草、艾蒿、山白竹及蒲公英所構成之花・葉菜類之酵母及/或乳酸菌發酵物 (e)昆布、海帶芽及海蘊所構成之海藻類之酵母及/或乳酸菌發酵物 (f)黑芝麻、胡桃及銀杏所構成之種子類之酵母及/或乳酸菌發酵物 (g)舞菇及香菇所構成之菇類之酵母及/或乳酸菌發酵物。 A metallo-β-lactamase inhibitor, which contains a plant fermentation product of a mixture of the following (a) to (g) as an active ingredient: (a) bean and cereal fermentation products composed of barley, black beans, red rice, black rice, red beans, coix, barley, millet and sorghum (b) fruit fermentation products composed of citrus, grapes, apples, purple kudzu, peaches, persimmons, papayas, pears, watermelons, plums, figs, light-skinned papayas, pumpkins, kumquats, grapefruits, loquats, apricots, dates, chestnuts, Polygonum multiflorum and plums (c) Yeast and/or lactic acid bacteria fermentation products of root vegetables and tubers including purple sweet potato, Jerusalem artichoke, carrot, onion, sweet potato, taro, Japanese yam, radish, red turnip, burdock, lotus root, Jerusalem artichoke, lily root, arrowhead, ginger, garlic and turmeric (d) Yeast and/or lactic acid bacteria fermentation products of flower and leaf vegetables including cabbage, perilla, mulberry leaf, houttuynia cordata, mugwort, mountain bamboo and dandelion (e) Yeast and/or lactic acid bacteria fermentation products of seaweed including kelp, kelp sprout and seaweed (f) Yeast and/or lactic acid bacteria fermentation products of seeds including black sesame, walnut and ginkgo (g) Yeast and/or lactic acid bacteria fermentation products of mushrooms including maitake and shiitake. 如請求項1之金屬-β-內醯胺酶抑制劑，其中植物發酵物，按植物發酵物每100g含有以下組成之胺基酸： 　　精胺酸 0.2~0.6g 　　離胺酸 0.1~0.7g 　　組胺酸 0.1~0.4g 　　苯丙胺酸 0.2~0.8g 　　酪胺酸 0.1~0.6g 　　白胺酸 0.3~1.2g 　　異白胺酸 0.2~0.8g 　　甲硫胺酸 0.05~0.30g 　　纈胺酸 0.2~0.9g 　　丙胺酸 0.2~0.9g 　　甘胺酸 0.2~0.7g 　　脯胺酸 0.4~1.2g 　　麩胺酸 1.2~3.0g 　　絲胺酸 0.2~0.8g 　　蘇胺酸 0.2~0.7g 　　天門冬胺酸 0.4~1.5g 　　色胺酸 0.03~0.15g 　　半胱胺酸 0.05~0.40g。
For example, the metallo-β-lactamase inhibitor of claim 1, wherein the plant fermentation contains the following amino acids per 100 g of the plant fermentation: 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 Glutamine 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 Cysteine 0.05~0.40g.
如請求項1之金屬-β-內醯胺酶抑制劑，其中植物發酵物，按植物發酵物每100g含有以下組成之有機酸： 　　檸檬酸 0.5~1.2g 　　蘋果酸 0.05~0.5g 　　琥珀酸 0.04~0.3g 　　乳酸 0.5~6.0g 　　甲酸 0.01~0.1g 　　丙酮酸 0.005~0.05g 　　游離γ-胺基丁酸 0.01~0.05g。
For example, in the metallo-β-lactamase inhibitor of claim 1, the plant fermentation contains the following organic acids per 100 g of the plant fermentation: Citric Acid 0.5~1.2g Apple acid 0.05~0.5g Succinic acid 0.04~0.3g Lactic acid 0.5~6.0g Formic acid 0.01~0.1g Pyruvate 0.005~0.05g Free GABA 0.01~0.05g.
如請求項1之金屬-β-內醯胺酶抑制劑，其中乳酸菌為選自由乳酸片球菌(P. acidilacti)、短乳酸菌(L. brevis)、腸膜明串珠菌(L. mesenteroides)、植物乳桿菌(L. plantarum)、乳酸乳球菌(L. lactis)、酒乳桿菌(L. sakei)、戊糖片球菌(P. pentosaceus)、乾酪乳桿菌(L. casei)及彎曲乳桿菌(L. curvatus)所成群組的1種或2種以上。The metallo-β-lactamase inhibitor of claim 1, wherein the lactic acid bacteria is one or more species selected from the group consisting of Pediococcus acidilacti, Lactobacillus brevis, Lactobacillus mesenteroides, Lactobacillus plantarum, Lactococcus lactis, Lactobacillus sakei, Pediococcus pentosaceus, Lactobacillus casei and Lactobacillus curvatus. 如請求項1之金屬-β-內醯胺酶抑制劑，其中酵母為釀酒酵母(S. cervisiae)及/或魯氏接合酵母(Z. rouxii)。The metallo-β-lactamase inhibitor of claim 1, wherein the yeast is brewing yeast (S. cervisiae) and/or Zygosaccharomyces rouxii (Z. rouxii). 一種抗多重抗藥性革蘭氏陰性菌用食品，其係含有如請求項1~5中任一項之金屬-β-內醯胺酶抑制劑。A food for use against multidrug-resistant Gram-negative bacteria, comprising the metallo-β-lactamase inhibitor of any one of claims 1 to 5. 一種抗多重抗藥性革蘭氏陰性菌用組成物，其係含有如請求項1~5中任一項之金屬-β-內醯胺酶抑制劑與抗菌藥。A composition for use against multidrug-resistant Gram-negative bacteria, comprising the metallo-β-lactamase inhibitor of any one of claims 1 to 5 and an antibacterial drug. 一種多重抗藥性革蘭氏陰性菌之控制方法，其特徵為對多重抗藥性革蘭氏陰性菌投予抗菌藥與如請求項1~5中任一項之金屬-β-內醯胺酶抑制劑。A method for controlling multidrug-resistant Gram-negative bacteria, characterized in that an antibacterial drug and a metallo-β-lactamase inhibitor according to any one of claims 1 to 5 are administered to the multidrug-resistant Gram-negative bacteria. 一種多重抗藥性革蘭氏陰性菌相關疾病之治療方法，其特徵為對患有多重抗藥性革蘭氏陰性菌相關疾病之動物投予抗菌藥與如請求項1~5中任一項之金屬-β-內醯胺酶抑制劑。A method for treating a disease associated with multidrug-resistant Gram-negative bacteria, characterized in that an antibacterial drug and a metallo-β-lactamase inhibitor according to any one of claims 1 to 5 are administered to an animal suffering from the disease associated with multidrug-resistant Gram-negative bacteria.
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