WO2023061416A1 - 一种组合物及其抗菌应用 - Google Patents

一种组合物及其抗菌应用 Download PDF

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WO2023061416A1
WO2023061416A1 PCT/CN2022/124947 CN2022124947W WO2023061416A1 WO 2023061416 A1 WO2023061416 A1 WO 2023061416A1 CN 2022124947 W CN2022124947 W CN 2022124947W WO 2023061416 A1 WO2023061416 A1 WO 2023061416A1
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composition
acid
glycine
staphylococcus aureus
escherichia coli
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PCT/CN2022/124947
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English (en)
French (fr)
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朱绍和
陈丽
宋坤坪
田雪晨
杨毅欣
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温州肯恩大学
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    • A—HUMAN NECESSITIES
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    • A01P—BIOCIDAL, PEST REPELLANT, PEST ATTRACTANT OR PLANT GROWTH REGULATORY ACTIVITY OF CHEMICAL COMPOUNDS OR PREPARATIONS
    • A01P1/00—Disinfectants; Antimicrobial compounds or mixtures thereof
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
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    • A01N37/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids
    • A01N37/02—Saturated carboxylic acids or thio analogues thereof; Derivatives thereof
    • A01N37/04—Saturated carboxylic acids or thio analogues thereof; Derivatives thereof polybasic
    • A—HUMAN NECESSITIES
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    • A01N37/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids
    • A01N37/06—Unsaturated carboxylic acids or thio analogues thereof; Derivatives thereof
    • A—HUMAN NECESSITIES
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    • A01N37/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids
    • A01N37/36—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids containing at least one carboxylic group or a thio analogue, or a derivative thereof, and a singly bound oxygen or sulfur atom attached to the same carbon skeleton, this oxygen or sulfur atom not being a member of a carboxylic group or of a thio analogue, or of a derivative thereof, e.g. hydroxy-carboxylic acids
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    • A01N37/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids
    • A01N37/44—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids containing at least one carboxylic group or a thio analogue, or a derivative thereof, and a nitrogen atom attached to the same carbon skeleton by a single or double bond, this nitrogen atom not being a member of a derivative or of a thio analogue of a carboxylic group, e.g. amino-carboxylic acids
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Definitions

  • the invention relates to the technical field of medicine, in particular to a composition and its antibacterial application.
  • Pangolin is used in the "Xiagging Huomingyin” in “Women's Prescription” written by Chen Ziming in the Song Dynasty.
  • the effects of the whole prescription include clearing away heat and detoxification, reducing swelling and ulceration, promoting blood circulation and relieving pain, etc., and local redness, swelling, heat and pain.
  • Li Shizhen's "Compendium of Materia Medica” in the Ming Dynasty records that pangolins "eliminate phlegm, malaria, cold and heat, wind numbness, stiffness and pain, open the meridians, relieve pain and swelling, expel pus and blood, clear the orifices and kill insects.” Divide pangolin and clam powder into equal parts, stir fry and grind into powder.
  • pangolins are used to treat some diseases that modern medicine believes are caused by bacterial infections. Guo Yi et al reported in the "Journal of Hunan University of Traditional Chinese Medicine" that pangolin decoction has antibacterial effect on 11 kinds of bacteria including Escherichia coli, and the main component of pangolin decoction is squamous scales.
  • pangolins are extremely endangered in modern society, eight species of pangolins have been included in the 2014 Red List of Endangered Species by the International Union for Conservation of Nature (IUCN), and in 2016 they were included in the CITES Appendix I protection of the Washington Convention. Animals, global trade banned. my country is a party to the Convention on International Trade in Endangered Species of Wild Fauna and Flora (CITES). At the same time, in 2020, the "Chinese Pharmacopoeia" will exclude pangolins from being used as medicine.
  • the present invention explores the ingredients or composition of ingredients in pangolin scales that inhibit the flora, and artificially synthesizes them as a substitute, so as to ensure that the relevant treatment plan that replaces the ingredients of the pangolin is not affected, and at the same time it can protect endangered species.
  • organic acid is used as an organic acid additive in various fields, among which citric acid is the most frequently used organic acid for antisepsis and flavor addition.
  • the Chinese patent with publication number CN108670897B relates to a high-efficiency antibacterial wet tissue composition and a preparation method thereof.
  • the raw materials for the preparation of the high-efficiency antibacterial wet tissue composition include, in parts by weight, 1-6 ethanol, 0.5-3 butanediol, 0.2-0.6 solubilizer, 0.01-0.02 menthol, 0.1-0.12 essence, and tea extract 0.5 to 1.0, olive leaf extract 0.5 to 1.0, nano silver, purslane extract 0.5 to 1.0, citric acid 0.1 to 0.2, sodium citrate 0.05 to 0.15, phenoxyethanol 0.01 to 0.05.
  • the component of the composition involves the organic acid citric acid, and uses it as an antibacterial component, wherein phenoxyethanol is used for the solubilization of the citric acid.
  • the existing organic acids are various, and the antibacterial effect of citric acid cannot reach the highest antibacterial efficiency among them.
  • the Chinese patent with the publication number CN108904374A relates to an oral cleanser, which includes: 3-8 parts by weight of tea extract, 1-3 parts of persimmon astringent, 1-2 parts of fructose, 2-4 parts of citric acid, spices 1-3 servings.
  • the pH value of mouthwash or other oral cleaning agents should be in the range of 6.5-7.5, and the pH value of this range tends to be neutral. In a neutral environment, the use of mouthwash will not destroy the protein in the oral cavity, and Can play a very good bactericidal effect.
  • Glycine buffer consisting of glycine is able to maintain liquid in the range of 2.2-10.6.
  • Pseudomonas aeruginosa and Serratia marcescens are immunocompromised opportunistic pathogens that frequently occur in wounds.
  • the oral cleanser prevents Pseudomonas aeruginosa and Serratia marcescens from entering the respiratory tract and causing harm to patients by inhibiting the growth of Pseudomonas aeruginosa and Serratia marcescens in the oral cavity.
  • the invention provides a composition.
  • the composition comprises: one or more of malic acid, hippuric acid, fumaric acid, glycine, succinic acid, L-valine and citric acid.
  • the ingredients in the composition comprise: (1) malic acid; (2) hippuric acid; (3) optionally at least one of the following weakly acidic ingredients: 1) glycine; 2) succinic acid and/or L-valeric acid acid.
  • the ingredients in the composition comprise: (1) malic acid; (2) hippuric acid; (3) optionally at least one of the following weakly acidic ingredients: 1) fumaric acid and/or glycine; 2) succinic acid and/or L-valine.
  • the first component composed of malic acid, hippuric acid, succinic acid, and L-valine is formulated together with the second component composed of fumaric acid or succinic acid to form a Compositions to achieve an inhibitory effect.
  • the advantage of this technical solution compared with the application of a single organic acid, the combination of organic acids formed by multiple combinations can form a better bacteriostatic effect than a single organic acid (confirmed by bacteriostatic tests), and through a variety of The combination of organic acids forms different flavors of disinfectant ingredients that are suitable for food, cosmetics, oral cleaning, etc. to act on the human body, achieving the purpose of deodorization and refreshing.
  • the formation and decomposition of organic acids are harmless to the human body and the environment.
  • the principle of antibacterial and sterilizing is to enter the bacteria in the form of small molecules and destroy the alkaline active environment in the bacteria, thereby inhibiting the activity of the bacteria.
  • the combination of organic acids of multiple combinations forms a covalent structure with each other, and forms a mutual augmented bacteriostatic effect, and replaces the organic acids that are randomly combined in a single or polymorphic way and require a large dose of addition with a smaller dose of the composition, thereby Reduce the harm of excessive intake of food additives to the human body.
  • said composition acting on the human body or the environment comprises malic acid, hippuric acid, glycine and citric acid, wherein the composition is based on the interaction of malic acid and citric acid being able to enhance the buffering of acidic senses For fruity ingredients that act on the environment.
  • the composition comprises at least malic acid, hippuric acid, glycine and citric acid, wherein the components constituting the composition are applied to the skin surface in the form of a non-Newtonian fluid.
  • the composition comprises at least malic acid, hippuric acid, glycine and fumaric acid, wherein the components constituting the composition are applied to the skin surface in the form of a non-Newtonian fluid.
  • the drugs and cosmetics used for the repair, treatment or protection of the skin surface cannot achieve stable attachment on the face due to the fluidity of the fluid during the application process, but the paste drug form is due to the viscosity Not easy to apply evenly.
  • the present invention adopts the component form of non-Newtonian fluid, which reduces its fluidity and does not change the viscosity, thereby ensuring the stability of the components on the face and skin.
  • the invention relates to a composition sprayed on the surface of the human body or the environment where the human body is located, which comprises the following substances: 1.2% malic acid, 0.3% hippuric acid, 0.2% citric acid, 0.1% glycine and the rest Water, the composition cleans the human body or the environment where the human body is located by inhibiting the reproduction of Escherichia coli and Staphylococcus aureus, wherein,
  • the minimum inhibitory concentration used by the composition to inhibit Escherichia coli and Staphylococcus aureus is higher than that used by 1.2% malic acid, 0.3% hippuric acid, 0.2% citric acid, and 0.1% glycine to inhibit Escherichia coli and Staphylococcus aureus alone
  • the minimum inhibitory concentration was 2.5 times lower.
  • the invention relates to the application of the composition comprising 1.2% malic acid, 0.3% hippuric acid, 0.2% citric acid, 0.1% glycine and the rest of water in detergent, antibacterial medicine or food.
  • the present invention relates to a bactericide.
  • the bactericide comprises a combined liquid or gas particle, the combined liquid or gas particle contains a particle core composed of highly effective antibacterial organic acid and a nano-scale inorganic microporous form covered by a silane coupling agent neutralized by a silane coupling agent.
  • the zirconia-tin oxide composite is used to protect and increase the adhesion ability of the outer film, so that the nano-scale inorganic microporous zirconia-tin oxide composite that is neutralized by the silane coupling agent wrapped in organic acids can Fog, aerosol or small particle liquid is dispersed in clothing and living environment, wherein the organic acid is configured as:
  • the mass percentage is 1.2% malic acid, 0.3% hippuric acid, 0.2% citric acid, 0.1% glycine and the rest of water.
  • the minimum inhibitory concentration used by the organic acid to inhibit Escherichia coli and Staphylococcus aureus is higher than that used by 1.2% malic acid, 0.3% hippuric acid, 0.2% citric acid or 0.1% glycine to inhibit Escherichia coli and Staphylococcus aureus alone
  • the minimum inhibitory concentration is 2.5 times lower, and the preparation method of the combined liquid or gas particles is as follows:
  • the present invention relates to a composition, which comprises: 0.1% fumaric acid, 1.2% malic acid, 0.3% hippuric acid, 0.1% glycine and the rest of water in mass percentage, wherein,
  • the minimum inhibitory concentration used by the composition to inhibit Escherichia coli and Staphylococcus aureus is higher than that used by 0.1% fumaric acid, 1.2% malic acid, 0.3% hippuric acid and 0.1% glycine to inhibit Escherichia coli and Staphylococcus aureus alone 2.5 times lower minimum inhibitory concentration.
  • the invention relates to the application of the composition comprising 0.1% fumaric acid, 1.2% malic acid, 0.3% hippuric acid, 0.1% glycine and the rest of water in detergent, antibacterial medicine or food.
  • the present invention relates to the composition that comprises the water of mass percentage 0.1% fumaric acid, 1.2% malic acid, 0.3% hippuric acid, 0.1% glycine and the remainder to inhibit Escherichia coli, Staphylococcus metallobacter, Pseudomonas aeruginosa and sara regards marcescens
  • the purposes in bacterial growth, wherein, described composition can reach the antibacterial effect of 0.1C to escherichia coli, staphylococcus metallobacter, Pseudomonas aeruginosa and Serratia marcescens.
  • the present invention relates to a bactericide.
  • the bactericide comprises a first composition with a bacteriostatic effect and a second composition that forms a gel network to wrap the application target of the first composition, and the first composition is configured as: 0.1% fumaric acid by mass percentage , 1.2% malic acid, 0.3% hippuric acid, 0.1% glycine and the rest of water, the molecular diameters of fumaric acid, malic acid, hippuric acid and glycine acting on the bacterial intracellular environment can be smaller than Escherichia coli and Staphylococcus aureus The diameter of the cell membrane channel, so that the first composition inhibits the activity of Escherichia coli and Staphylococcus aureus based on the change of the alkaline environment inside the bacterial cell, and the first composition inhibits the activity of Escherichia coli and Staphylococcus aureus
  • the minimum inhibitory concentration used is 2.5 times lower than the minimum inhibitory concentration used to inhibit Escherichia
  • the second composition is configured as: a hydrocolloid comprising polysaccharides and proteins, wherein,
  • the second composition is capable of enveloping an object to which the first composition is applied, and the first composition mixed in the second composition is capable of entering based on pressure formed on the object to which the first composition is applied.
  • the target is inside, and H + is released inside the target, destroying the alkaline environment inside the bacterium and inhibiting the activity of the bacterium.
  • the invention relates to a composition for inhibiting the growth of drug-resistant bacteria.
  • the composition comprises: 512 ⁇ g/ml malic acid, 32 ⁇ g/ml fumaric acid and 512 ⁇ g/ml glycine, wherein the composition can inhibit the growth of 99% drug-resistant Acinetobacter baumannii and inhibit 90% drug-resistant Staphylococcus aureus growth.
  • the invention relates to the use of the composition for inhibiting the growth of drug-resistant bacteria in inhibiting the growth of methicillin-resistant bacterial strains.
  • the invention relates to the use of the composition for inhibiting the growth of drug-resistant bacteria in inhibiting the growth of carbapenem antibiotic-resistant bacterial strains.
  • the present invention relates to a pharmaceutical composition.
  • the pharmaceutical composition comprises 512 ⁇ g/ml malic acid, 32 ⁇ g/ml fumaric acid, 512 ⁇ g/ml glycine and optional pharmaceutically acceptable auxiliary materials.
  • the invention relates to a composition capable of inhibiting Acinetobacter baumannii with carbapenem antibiotic resistance and Staphylococcus aureus with methicillin resistance.
  • the composition contained 512 ⁇ g/ml malic acid, 32 ⁇ g/ml fumaric acid and 512 ⁇ g/ml glycine.
  • the invention relates to a composition capable of inhibiting Acinetobacter baumannii with carbapenem antibiotic resistance and Staphylococcus aureus with methicillin resistance.
  • the composition comprises 512 ⁇ g/ml malic acid, 512 ⁇ g/ml fumaric acid, 512 ⁇ g/ml glycine and 512 ⁇ g/ml hippuric acid.
  • the invention relates to a pharmaceutical composition for bacterial pulmonary infection.
  • the pharmaceutical composition comprises: malic acid, hippuric acid, fumaric acid and glycine.
  • the dosage of the pharmaceutical composition for bacterial pulmonary infection is 0.5 g ⁇ kg -1 d -1 to 1.5 g ⁇ kg -1 d -1 .
  • the composition can inhibit the division of Escherichia coli and Staphylococcus aureus in a synergistic manner.
  • a composition which can constitute a cleaning component of an oral cleaning agent in the form of a dispersed phase and an abrasive, and the composition is used to inhibit the growth of Escherichia coli and Staphylococcus aureus in the oral cavity, wherein the composition contains malic acid , hippuric acid, fumaric acid, glycine, succinic acid, L-valine and citric acid in one or more.
  • a composition capable of inhibiting the propagation of Escherichia coli and Staphylococcus aureus on the surface of human skin or in food wherein the composition contains malic acid, hippuric acid, fumaric acid, glycine, succinic acid, L - One or more of valine and citric acid.
  • Antibacterial application of a composition which is applied as an additive in a detergent or a bactericide, said composition as an additive is provided with a first composition for releasing H + and for increasing the killing effect and time second composition.
  • the first composition includes: one or more of malic acid, hippuric acid, fumaric acid, glycine, succinic acid, L-valine and citric acid, and the second composition includes hydrocolloid.
  • the first composition intervenes in the second composition, and accompanied by the second composition on the E. Staphylococcus encapsulation acts on the inside of Escherichia coli or Staphylococcus aureus.
  • An antibacterial application of a composition characterized in that it is used as a growth inhibitory drug for bacteria in bacterial lung infection, and the main components of the drug include: malic acid, hippuric acid, fumaric acid, glycine, succinic acid, One or more of L-valine and citric acid.
  • Fig. 1 is the schematic diagram of the influence result of the metabolite combination of different concentrations in the present invention on the growth of escherichia coli, Staphylococcus metallobacter, Pseudomonas aeruginosa and Serratia marcescens;
  • Fig. 2 is the result schematic diagram of the inhibition rate of Acinetobacter baumannii and Staphylococcus aureus respectively for different combinations of high concentration components;
  • Fig. 3 is the time sterilizing curve of drug-resistant Acinetobacter baumannii in combination with two, three and four components;
  • Fig. 4 is two, three and four-component joint combination combination to the time bactericidal curve figure of methicillin-resistant Staphylococcus aureus;
  • Figure 5 is a schematic diagram of the impact of low, medium and high dose metabolite combinations and ciprofloxacin on the lung bacterial load of the mouse lung infection model caused by Escherichia coli;
  • Fig. 6 is an HE staining diagram of mouse lung tissue after treatment with low, medium and high doses of the metabolic composition and ciprofloxacin.
  • the invention designs an antibacterial composition, which can realize the most effective inhibition on microorganisms represented by Escherichia coli and Staphylococcus aureus.
  • Organic acids used for antibacterial include Fumaric acid, Succinic acid, L-Valine, Malic acid, Citric acid, Glycine ( Glycine) and hippuric acid (Hippuric acid). Its ratio is consistent with the content in pangolin scales. Among them, in the total extract (CV), fumaric acid accounts for 0.1%, succinic acid accounts for 0.4%, L-valine accounts for 1.3%, and malic acid accounts for 1.2%. %, citric acid accounted for 0.2%, glycine accounted for 0.1% and hippuric acid accounted for 0.3%. Preferably, the above ratio is adjustable and effective.
  • microorganisms involved in this paper can include Gram-negative bacteria, Gram-positive bacteria, or include Staphylococcus aureus as the representative of pathogenic Staphylococcus, Escherichia coli as the representative of conditional pathogenic bacteria or other pathogenic bacteria, Such as Mycobacterium tuberculosis.
  • the organic acids used in the experiments and composition components of the present invention are all synthetic organic acids.
  • Antibacterial tests were carried out based on the minimum inhibitory concentration method (MIC), and the above antibacterial metabolites were used for Escherichia coli (E.coli; Escherichia coli) and Staphylococcus aureus (S.aureus; Staphylococcus aureus), Pseudomonas The minimum inhibitory concentration (MIC; Minimum Inhibitory Concentration) detection of P.aeruginosa; Pseudomonas aeruginosa) and Serratia marcescens (S.marcescens; Serratia marcescens).
  • MIC Minimum Inhibitory Concentration
  • Lysogeny Broth (LB; Lysogeny Broth) medium containing 10 g/L peptone, 5 g/L yeast extract and 10 g/L sodium chloride was used.
  • the whole composition comprises one or more of fumaric acid, succinic acid, L-valine, malic acid, citric acid, glycine and hippuric acid.
  • the preserved Escherichia coli representing Gram-negative bacteria and Staphylococcus aureus representing Gram-positive bacteria were resuscitated simultaneously.
  • malic acid and fumaric acid has weak antibacterial effect when combined with L-valine or citric acid.
  • malic acid and L-valine have the same results when combined with glycine or hippuric acid , the inhibitory effect on Escherichia coli and Staphylococcus aureus weakened, and the MIC value rose back to 0.4C.
  • the combination of malic acid, hippuric acid and citric acid has the best inhibitory effect on Escherichia coli, with an MIC value of 0.1C.
  • malic acid was selected as the main component, and four compositions were formed by assigning other metabolites and malic acid to conduct antibacterial tests. The results are shown in Table 4.
  • malic acid was selected as the main component, and five compositions composed of other metabolites and malic acid were selected for antibacterial test. The results are shown in Table 5.
  • malic acid was selected as the main component, and six compositions and seven metabolites were mixed by assigning other metabolites and malic acid to conduct antibacterial tests. The results are shown in Table 6.
  • the organic acid metabolite composition composed of malic acid, hippuric acid, fumaric acid and glycine has antibacterial properties against bacteria represented by Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa and Serratia marcescens, especially pathogenic bacteria inhibition of its growth.
  • Serratia marcescens is the smallest bacterium, a Gram-negative bacillus, and an opportunistic pathogen.
  • Pseudomonas aeruginosa is a gram-negative bacterium that is an opportunistic infection.
  • Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa and Serratia marcescens are widely distributed in nature. They can enter the human body through the mouth and nose of the human body, and cause inflammation and other pathogenic reactions in the human body under certain conditions or environmental conditions. Therefore, in this experiment, the above four strains were selected as the test objects of the antibacterial test.
  • composition composed of malic acid, glycine and hippuric acid can be combined with citric acid or fumaric acid to form an antibacterial effect on Staphylococcus aureus and Escherichia coli with an MIC value of 0.1C.
  • the proportions in the composition used in the experiment above can be 0.1% for fumaric acid, 0.4% for succinic acid, 1.3% for L-valine, 1.2% for malic acid, and 0.2% for citric acid. %, glycine accounted for 0.1% and hippuric acid accounted for 0.3%, and the antibacterial composition was prepared in the above proportions.
  • the composition for reducing the reproduction tendency of microorganisms existing on the surface of the human body or in the environment where the human body is located comprises: 0.125%-0.482% malic acid, 0.135%-0.422% L-valine, 0.021%-0.081% One or more of citric acid, 0.01%-0.04% succinic acid, 0.031%-0.121% hippuric acid, 0.001%-0.041% glycine and 0.01%-0.041% fumaric acid.
  • the ratio of each component in the composition can be: malic acid accounts for 1% to 30% of the total components, L-valine accounts for 0.1% to 20% of the total components, citric acid Accounting for 0.1%-20% of the total components, 0.1%-20% for succinic acid, 0.1%-20% for hippuric acid, and 0.1%-20% for glycine The ratio is 0.1% to 20% and fumaric acid accounts for 0.1% to 20% of the total components.
  • the ratio of each component in the composition can be: malic acid accounts for 10% to 40% of the total components, L-valine accounts for 0.01% to 10% of the total components, citric acid Accounting for 0.01%-10% of the total components, 0.01%-20% for succinic acid, 0.01%-20% for hippuric acid, and 0.01%-20% for glycine The ratio is 0.01% to 20% and fumaric acid accounts for 0.01% to 10% of the total components.
  • the malic acid can range from about 0.1% to about 20%, about 1% to about 10%, about 3% to about 8%, about 6% to about 12%, about In the range of 15% to about 18%, about 17% to about 20%, 20% to 60%, or by weight about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 15%, about 20%, about 30%, or about 40%, including all ranges and subranges therebetween.
  • the L-valine can range from about 0.01% to about 1%, from about 1% to about 10%, from about 3% to about 8%, from about 6% to about 12% by weight in the total components. %, about 15% to about 18%, about 17% to about 20%, or about 1%, about 2%, about 3%, about 4%, about 5%, about 6% by weight, About 7%, about 8%, about 9%, about 10%, about 15%, about 20%, about 30%, or about 40%, including all ranges and subranges therebetween.
  • the citric acid can range from about 0.01% to about 2%, about 1% to about 10%, about 3% to about 8%, about 6% to about 12%, about In the range of 15% to about 18%, about 17% to about 20%, or about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7% by weight , about 8%, about 9%, about 10%, about 15%, about 20%, about 30%, or about 40%, including all ranges and subranges therebetween.
  • the succinic acid can range from about 0.1% to about 20%, about 1% to about 10%, about 3% to about 8%, about 6% to about 12%, about In the range of 15% to about 18%, about 17% to about 20%, or about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7% by weight , about 8%, about 9%, about 10%, about 15%, about 20%, about 30%, or about 40%, including all ranges and subranges therebetween.
  • the hippuric acid can comprise from about 0.1% to about 20%, about 1% to about 10%, about 3% to about 8%, about 6% to about 12%, about In the range of 15% to about 18%, about 17% to about 20%, 20% to 60%, or by weight about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 15%, about 20%, about 30%, or about 40%, including all ranges and subranges therebetween.
  • the glycine can range from about 0.1% to about 2%, about 1% to about 10%, about 3% to about 8%, about 6% to about 12%, about 15% by weight of the total components % to about 18%, about 17% to about 20%, or by weight about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, About 8%, about 9%, about 10%, about 15%, about 20%, about 30%, or about 40%, including all ranges and subranges therebetween.
  • the fumaric acid can range from about 0.01% to about 20%, about 1% to about 10%, about 3% to about 8%, about 6% to about 12%, In the range of about 15% to about 18%, about 17% to about 20%, or about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7% by weight %, about 8%, about 9%, about 10%, about 15%, about 20%, about 30%, or about 40%, including all ranges and subranges therebetween.
  • the combination range of malic acid, L-valine, citric acid, succinic acid, hippuric acid, glycine and fumaric acid can include but not limited to the above ratio and combination range.
  • the composition with MIC value reaching 0.1C for Escherichia coli is represented by the composition of malic acid, hippuric acid and citric acid, while the composition with MIC value reaching 0.1C for Escherichia coli and Staphylococcus aureus at the same time
  • the composition is represented by malic acid, fumaric acid, glycine, hippuric acid; malic acid, citric acid, glycine, hippuric acid. Since the above-mentioned components forming the composition are all weakly acidic components and can be absorbed by the human body as food additives, the above-mentioned multi-group composition can be used in various fields as components that are harmless to the human body.
  • any organic acid has antibacterial effect, and it is added in large doses within the scope permitted by law to antibacterial That's it.
  • organic acids when organic acids are used as additives in large quantities, conversion products will be produced in the body. Small doses rely on metabolism, but large doses cannot guarantee that all products can be metabolized out of the body in a timely manner. bodily harm.
  • the present invention obtains the optimal bacteriostatic composition through the bacteriostatic ratio of effective bacteriostatic organic acids, and can reduce the amount of edible organic acids by increasing the types of edible organic acids, thereby helping food or other While ensuring the antiseptic effect, it will have a healthier impact on the human body.
  • Embodiment 1 is a further improvement on Embodiment 1, and repeated content will not be repeated here.
  • Liyan Tablets can have a better effect on the disease.
  • the ingredients of Liyan Tablets include pangolin (manufactured), wood beetle, silkworm, oyster (calcined), and scrophulariaceae.
  • pangolin (made) in the ingredients is taken from endangered organisms. This ingredient is a banned drug, so Liyan Tablets cannot be used. Treat patients as prescription or over-the-counter medicines.
  • the present invention explores the inhibitory effect on bacterial flora in pangolin scales, especially Escherichia coli and Staphylococcus aureus, and finds one or more groups of compositions that have effective inhibitory effects on Escherichia coli and Staphylococcus aureus.
  • the main components of the medicine include: one or more of malic acid, hippuric acid, fumaric acid, glycine, succinic acid, L-valine and citric acid.
  • the replacement ingredients can use biological tissue extracts with similar ingredients, and on the other hand, the replacement ingredients can also be artificially synthesized effective antibacterial metabolite substitute ingredients.
  • the synthetic compound when used as the replacement component, it can have the best inhibitory effect on Gram-negative bacteria represented by Escherichia coli and Gram-positive bacteria represented by Staphylococcus aureus designed in this experiment
  • Gram-negative bacteria represented by Escherichia coli
  • Gram-positive bacteria represented by Staphylococcus aureus designed in this experiment
  • One of the compositions malic acid, fumaric acid, succinic acid, L-valine, citric acid and glycine.
  • the addition of the above-mentioned organic acid can also bring fruity and other flavors popular to children to the tablet, thereby increasing the enthusiasm of infants and young children to take medicine.
  • Embodiment 1 is a further improvement on Embodiment 1 or Embodiment 2, and repeated content will not be repeated here.
  • the composition is also used in various foods as an additive composition to effectively inhibit Escherichia coli and Staphylococcus aureus in foods.
  • adding it to some natural fruit juices increases the natural flavor through the ratio of malic acid and citric acid, and cooperates with the fruit juice in vacuum or sealed packaging to achieve antiseptic effect by inhibiting the growth of Escherichia coli and Staphylococcus aureus.
  • the main components of the additive include: one or more of malic acid, hippuric acid, fumaric acid, glycine, succinic acid, L-valine and citric acid. Malic acid and citric acid alone or in combination form an additive with a fruity flavor.
  • Embodiment 1 is a further improvement on Embodiment 1, Embodiment 2 or Embodiment 3, and repeated content will not be repeated.
  • the composition can also be used in households or to disinfect bacteria under normal living conditions. For example, in home life, it is necessary to maintain antibacterial bacteria in the environment or clean clothes antibacterially, especially Staphylococcus aureus, which is harmful to the human body.
  • the disinfection of alcohol or 84 disinfectant is also harmful to the human body, and it is not suitable for families with pregnant women or children.
  • the present invention can form a liquid reagent for disinfecting bacteria suitable for families with children or pregnant women based on the composition of the weakly acidic component and other harmless bacteria-killing components.
  • compositions composed of organic acids can be used as additives in detergents or bactericides.
  • the composition as an additive is used for antibacterial and deodorizing of clothes or environment.
  • the composition is provided with a first composition as a pH regulator and a second composition for increasing the disinfecting effect and time.
  • the first composition comprises any one of two combinations: malic acid, glycine, hippuric acid, citric acid; malic acid, glycine, hippuric acid, fumaric acid.
  • the second composition comprises a hydrocolloid.
  • Hydrocolloids comprising polysaccharides and proteins form a gel network.
  • the first composition present in the hydrocolloid enters the bacterial cell from the cell based on the pressure of the gel network on the cell.
  • the first composition and the second composition work together to form a synergistic organic acid, release H + inside the cell, destroy the alkaline environment inside the cell, and thereby inhibit the activity of the cell.
  • the first composition intervenes in hydrocolloid, and acts on the inside of Escherichia coli or Staphylococcus aureus along with the encapsulation of Escherichia coli or Staphylococcus aureus carried by the target of detergent or bactericide application by the hydrocolloid.
  • the molecular diameter of the organic acid used to act on the bacterial intracellular environment can be smaller than the diameter of the cell membrane channel of Escherichia coli and Staphylococcus aureus so that the organic acid molecule can enter the inside of the cell through the cell membrane channel and destroy the alkalinity inside the cell
  • the environment inhibits bacterial cell activity.
  • the synergistic effect of the first composition composed of malic acid, glycine and hippuric acid and the second composition composed of citric acid or fumaric acid is realized.
  • Embodiment 1 is a further improvement on Embodiment 1, Embodiment 2, Embodiment 3 or Embodiment 4, and repeated content will not be repeated.
  • the present invention designs a composition, which is used to spread to the target surface by spraying, atomizing or other means of forming small particle gas or liquid, and disinfecting and inhibiting Escherichia coli and Staphylococcus aureus on the target surface.
  • Compositions consist of combined liquid or gaseous particles.
  • the above-mentioned liquid or gas particles contain a particle core composed of an efficient antibacterial organic acid and a nano-scale inorganic microporous zirconia-tin oxide composite covering the particle core that is neutralized by a silane coupling agent for protection and protection. Outer mantle for increased adhesion.
  • the nano-scale inorganic microporous zirconia-tin oxide composite that is neutralized by the silane coupling agent that wraps the organic acid is dispersed in the clothes and living environment in the form of aerosol, aerosol or small particle liquid.
  • the zirconia-tin oxide complex in nanoscale inorganic microporous form which is neutralized by the silane coupling agent of the acid, touches Escherichia coli and Staphylococcus aureus on the target surface, the outer film releases organic acids based on pressure and allows the organic acids to pass through the bacteria The cell membrane on the surface enters the bacterial body, thereby inhibiting bacterial activity.
  • the nanoscale inorganic micropores formed by the zirconia-tin oxide composite can allow organic acid molecules to enter and exit, and limit the hindrance of the decomposition and attachment of large-volume particles to the particles.
  • the zirconia-tin oxide composite can effectively maintain the hardness of the outer coating and the toughness of preventing nano-micropore collapse when forming the outer coating of particles in the form of aerosol, liquid or gas.
  • the ratio of the silane coupling agent to the nanoscale inorganic microporous zirconia-tin oxide composite is 1:40-1:120.
  • the ratio of nanoscale inorganic microporous zirconia-tin oxide composite to organic acid is between 1:1 and 1:10.
  • Microparticles composed of organic-inorganic bodies coupled with silane coupling agents can move to the target surface with a diameter of at least less than 10 ⁇ m.
  • the above-mentioned microparticles have excellent dispersion stability in the water phase for dilute or homogeneous liquid phase, high adhesion rate of carrying organic acid on the target surface, and high volatility performance of reducing the core of organic acid due to the wrapping of the outer film.
  • the coupling with a silane coupling agent can be coupling with an aqueous silane coupling agent.
  • the concentrated composition can be diluted with water before use, and then sprayed on the target surface requiring disinfection such as the environment or clothing through equipment such as an aerosol machine and a watering can.
  • the organic acid at the core of the above particles can be combined with the organic acid composition mentioned in the above examples that can have an bacteriostatic effect on Escherichia coli and Staphylococcus aureus with an MIC of 0.1C.
  • the combination of organic acids covered by the outer film involved in the present invention has good stability in water, and has high-efficiency inhibitory effect on Escherichia coli and Staphylococcus aureus.
  • Embodiment 1 is a further improvement on Embodiment 1, Embodiment 2, Embodiment 3, Embodiment 4 or Embodiment 5, and repeated content will not be repeated.
  • the present invention can design a composition containing one of malic acid, hippuric acid, fumaric acid, glycine, succinic acid, L-valine and citric acid.
  • One or more antibacterial ointments or sprays which can act on the skin surface or mucous membranes such as the face, arms, and vital organs.
  • the organic acid composition has obvious antibacterial effect on the reproduction of various pathogenic skin bacteria such as Escherichia coli and Staphylococcus aureus as representatives of Gram-negative bacteria and Gram-positive bacteria.
  • the antibacterial ointment includes traditional Chinese medicine ointment, traditional Chinese medicine powder, mussel mucin and one or more of malic acid, hippuric acid, fumaric acid, glycine, succinic acid, L-valine and citric acid.
  • traditional Chinese medicine ointment traditional Chinese medicine powder
  • mussel mucin one or more of malic acid, hippuric acid, fumaric acid, glycine, succinic acid, L-valine and citric acid.
  • the antibacterial spray contains pentylene glycol, 1,3 propylene glycol and one or more of malic acid, hippuric acid, fumaric acid, glycine, succinic acid, L-valine and citric acid organic acid composition.
  • the composition composed of malic acid, hippuric acid, fumaric acid and glycine has a significant effect on Escherichia coli (E. ), Pseudomonas aeruginosa (P.aeruginosa) and Serratia marcescens (S.marcescens) growth.
  • E. Escherichia coli
  • P.aeruginosa Pseudomonas aeruginosa
  • Serratia marcescens S.marcescens
  • composition composed of malic acid, hippuric acid, fumaric acid and glycine has a strong antibacterial effect on Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa and Serratia marcescens.
  • FIG. 1 The four line graphs of e, f, g, and h in Fig. 1 show that the composition composed of malic acid, hippuric acid, fumaric acid and glycine has the effect of MIC concentration on E.
  • Figure i in Figure 1 is the SEM image of the composition composed of malic acid, hippuric acid, fumaric acid and glycine against Escherichia coli and Staphylococcus aureus at MIC, 24h.
  • the four line graphs of e, f, g, and h in Figure 1 show that within 12 hours of the administration of the composition composed of malic acid, hippuric acid, fumaric acid and glycine, compared with the control group that did not apply the composition, the large intestine
  • the growth and amplification of Bacillus, Staphylococcus aeruginosa, Pseudomonas aeruginosa and Serratia marcescens were inhibited, and their OD values remained unchanged.
  • composition composed of malic acid, hippuric acid, fumaric acid and glycine especially the composition composed of 0.1% fumaric acid, 1.2% malic acid, 0.3% hippuric acid and 0.1% glycine can pass the inhibition of large intestine Bacillus, Staphylococcus metallo, Pseudomonas aeruginosa and Serratia marcescens grow to control the number of microbial flora in the environment, so as to achieve the effect of antibacterial disinfection.
  • the present invention also carries out the research on the optimal bacteriostasis combination screening of multi-component compounds and its time bactericidal curve.
  • drug-resistant bacteria used for antibacterial experiments, and the composition with good inhibitory effect on drug-resistant bacteria in the present invention is obtained.
  • Drug-resistant bacteria used Acinetobacter baumanni (A cinetobacter baumanni) and Staphylococcus aureus (Staphylococcus aureus).
  • Acinetobacter baumannii is resistant to carbapenem antibiotics, and its microbial strain number is bio-53272.
  • Staphylococcus aureus is resistant to methicillin, and its microbial strain number is ATCC BAA-1556.
  • the invention measures the single-component MIC of two drug-resistant bacteria to find the optimal drug combination and its optimal concentration.
  • test method includes four experimental processes of bacterial MIC determination, composition component screening, concentration screening and multiple screening.
  • the single-component MIC determination of two drug-resistant bacteria was carried out according to the antimicrobial susceptibility testing standard (CLSI-M100) of the American Clinical and Laboratory Standardization Association, and the specific steps were as follows:
  • OD reading at 9:00 on the third day Take out the 96-well plate from the incubator, determine the MIC value based on the turbidity, and then use a microplate reader to measure the OD value of the bacterial solution in the well plate at 595nm.
  • Table 8 is the minimum inhibitory concentration (MIC) of the four components to two kinds of bacteria. According to Table 8, the MIC value of each component is greater than 512 ⁇ g/ml, so each component is selected as 512 ⁇ g/ml as the highest test concentration, and each component is used in combination to test the inhibition of each combination on two kinds of bacteria effect to screen the optimal combination of components.
  • MIC minimum inhibitory concentration
  • OD reading at 9:00 on the third day Take out the 96-well plate from the incubator, determine the MIC value according to the turbidity, and then use a microplate reader to measure the OD value of the bacterial solution at 595nm.
  • Table 9 shows the inhibitory rates of the combination of the two components against Acinetobacter baumannii and Staphylococcus aureus at high concentrations (512 ⁇ g/ml), where the highlighted combination in the table is the optimal combination selected.
  • the double composition composed of 512 ⁇ g/ml fumaric acid and 512 ⁇ g/ml glycine can produce the best antibacterial effect on drug-resistant Staphylococcus aureus.
  • the PF-13 combination had the best effect in the combination of the two components, but it failed to achieve complete inhibition.
  • the double composition of 512 ⁇ g/ml malic acid and 512 ⁇ g/ml glycine can produce the best antibacterial effect on drug-resistant Acinetobacter baumannii.
  • the concentration of each component is 512 ⁇ g/ml
  • none of the compositions can achieve a complete inhibitory effect.
  • the PF-23 combination in the two-component combination combination is better (Inhibits about 70% of bacterial growth).
  • fractional inhibitory concentration test was performed on the combinations whose inhibition rate was higher than 90%, in order to obtain the optimal concentration of each component. Specific steps are as follows:
  • OD reading at 9:00 on the third day Take out the 96-well plate from the incubator, determine the MIC value according to the turbidity, and then use a microplate reader to measure the OD value of the bacterial solution at 595nm.
  • Table 10 shows the inhibitory rates of the combination of three and four components against Acinetobacter baumannii and Staphylococcus aureus at high concentrations (512 ⁇ g/ml), and the highlights in the table are the optimal combinations selected.
  • the results show that the triple composition consisting of 512 ⁇ g/ml malic acid, 512 ⁇ g/ml glycine and 512 ⁇ g/ml fumaric acid can produce the most effective antibacterial activity against drug-resistant Acinetobacter baumannii and drug-resistant Staphylococcus aureus. Excellent antibacterial effect.
  • the quadruple composition composed of 512 ⁇ g/ml malic acid, 512 ⁇ g/ml fumaric acid, 512 ⁇ g/ml glycine and 512 ⁇ g/ml hippuric acid can produce 100 % and 94.18% antibacterial effect.
  • PF-123 can completely inhibit the three-component combination, and PF-134 can inhibit about 90% of bacterial growth. This result also proved that the synergistic effect of PF-1 and PF-3 is an important part of its antibacterial effect.
  • the three-component combination of PF-123 inhibited about 90% of bacterial growth.
  • PF-1 is malic acid.
  • PF-2 is fumaric acid.
  • PF-3 is glycine.
  • PF-4 is hippuric acid.
  • PF-2 512 ⁇ g/ml
  • PF-3 512 ⁇ g/ml
  • PF-23 achieves an inhibition rate of about 70%
  • PF-123 and PF-1234 the concentration of each component is 512 ⁇ g/ml
  • 90% of the bacterial growth has been inhibited, because there is no complete inhibition (no growth above the detection line)
  • it is selected as the optimal concentration combination.
  • Figure 2 shows the inhibition rates of different combinations of high concentrations (512 ⁇ g/ml) on Acinetobacter baumannii Staphylococcus aureus.
  • PF-1234 For drug-resistant Acinetobacter baumannii, the combination of four components, namely PF-1234, can completely inhibit the growth of bacteria. Since PF-123 and PF-1234 show complete inhibition, it is necessary to test the minimum required concentration of each component, that is, the optimal component concentration.
  • the four-component combination of PF-1234 inhibited about 90% of bacterial growth. Since the antibacterial effects of PF123 and PF-1234 are the same, the optimal concentration combination is PF-123.
  • Fig. 3 shows: two, three and four components are combined to the time sterilization curve of drug-resistant Acinetobacter baumannii, wherein, MNT refers to the mixture of MHB and bacterium liquid, PF-13 (512 ⁇ g/ml PF-1 +512 ⁇ g/ml PF-3) refers to the optimal concentration of the two components combined; PF-123 (512 ⁇ g/ml PF-1+32 ⁇ g/ml PF-2+512 ⁇ g/ml PF-3) refers to the optimal concentration of the three components Combined use; PF-1234 (512 ⁇ g/ml PF-1+32 ⁇ g/ml PF-2+512 ⁇ g/ml PF-3+32 ⁇ g/ml PF-4) refers to the combination of the optimal concentrations of the four components.
  • MNT refers to the mixture of MHB and bacterium liquid
  • PF-13 512 ⁇ g/ml PF-1 +512 ⁇ g/ml PF-3 refers to the optimal concentration of the two components
  • Figure 4 shows: two, three and four-component combined combination combined with the time bactericidal curve of methicillin-resistant Staphylococcus aureus
  • MNT refers to the mixture of MHB and bacterial liquid
  • PF-23 512 ⁇ g/ml PF -2+512 ⁇ g/ml PF-3) refers to the optimal concentration of the two components combined
  • PF-123 512 ⁇ g/ml PF-1+512 ⁇ g/ml PF-2+512 ⁇ g/ml PF-3) refers to the optimal Combined use at optimal concentrations
  • PF-1234 (512 ⁇ g/ml PF-1+512 ⁇ g/ml PF-2+512 ⁇ g/ml PF-3+512 ⁇ g/ml PF-4) refers to the combination of four components at optimal concentrations.
  • the PF-23 combination has a lower inhibition rate than the combination of three and four components, which is well reflected in the time killing curve.
  • PF-1, PF-2, and PF-3 have a certain synergistic effect on each other, and the contribution of PF-1 to the synergistic effect is slightly smaller than that of the other two components, while the contribution of PF-4 Addition has the least effect on synergy.
  • PF-123 can inhibit methicillin-resistant Staphylococcus aureus and drug-resistant Acinetobacter baumannii.
  • the present invention provides a composition for inhibiting the growth of drug-resistant bacteria, said composition comprising: 512 ⁇ g/ml malic acid, 32 ⁇ g/ml fumaric acid and 512 ⁇ g/ml glycine, wherein said composition can Inhibit 99% of the growth of drug-resistant Acinetobacter baumannii, and inhibit the growth of 90% of drug-resistant Staphylococcus aureus.
  • composition for inhibiting the growth of drug-resistant bacteria provided by the present invention can be used to inhibit the growth of methicillin-resistant bacterial strains and has applications in medicines or daily necessities for inhibiting the growth of methicillin-resistant bacterial strains.
  • composition for inhibiting the growth of drug-resistant bacteria provided by the present invention can be used to inhibit the growth of carbapenem-resistant bacterial strains and has applications in medicines or daily necessities for inhibiting the growth of carbapenem-resistant bacterial strains.
  • the present invention provides a pharmaceutical composition.
  • the pharmaceutical composition comprises 512 ⁇ g/ml malic acid, 32 ⁇ g/ml fumaric acid, 512 ⁇ g/ml glycine and optional pharmaceutically acceptable auxiliary materials.
  • the dosage forms of the pharmaceutical composition include: oral preparations, injection preparations, transdermal administration preparations, mucosal administration preparations, pulmonary inhalation administration preparations or enteral administration preparations.
  • the dosage forms of the pharmaceutical composition include: drops, oral liquids, tablets, capsules, granules, granules, films, gels, powders, emulsions, drop pills, suppositories, gas Mist, spray, powder, patch, plaster, solution, ointment, or cream.
  • the present invention provides a composition capable of inhibiting Acinetobacter baumannii with carbapenem antibiotic resistance and Staphylococcus aureus with methicillin resistance, said The composition contained 512 ⁇ g/ml malic acid, 32 ⁇ g/ml fumaric acid and 512 ⁇ g/ml glycine.
  • the present invention provides a composition capable of inhibiting Acinetobacter baumannii with carbapenem antibiotic resistance and Staphylococcus aureus with methicillin resistance, said The composition contained 512 ⁇ g/ml malic acid, 512 ⁇ g/ml fumaric acid, 512 ⁇ g/ml glycine and 512 ⁇ g/ml hippuric acid.
  • Acinetobacter baumannii can cause bacteremia, pneumonia, meningitis, peritonitis, endocarditis, and urinary tract and skin infections.
  • Acinetobacter baumannii has become a major source of nosocomial infections, especially in intensive care units. Due to the abuse of antibiotics, the bacteria have become resistant to antibiotics and become "multi-drug resistant Acinetobacter baumannii". The only way to fight multi-drug resistant Acinetobacter baumannii is with late-line antibiotics like tiger mycin.
  • the composition of the present invention can be used to inhibit drug-resistant Acinetobacter baumannii, especially for patients who may be infected with Acinetobacter baumannii.
  • Methicillin-resistant Staphylococcus aureus can cause multiple infections in the human body, including respiratory tract infection, post-operative infection, ENT infection, burn or post-traumatic infection, etc.
  • This methicillin-resistant Staphylococcus aureus is resistant to many common clinical antibiotics, including penicillins, macrolides, tetracyclines, and cephalosporins.
  • the composition of the present invention can be used to inhibit methicillin-resistant Staphylococcus aureus, especially for patients who may be infected with Staphylococcus aureus.
  • composition PF-123 or PF-1234 in the present application can be applied in the body of the patient, on the surface of the body or in its environment in the form of medicine.
  • the present application relates to a composition for bacterial lung infection.
  • the low, medium and high doses of the metabolic composition are respectively: 0.5 g ⁇ kg -1 d -1 , 1.0 g ⁇ kg -1 d -1 and 1.5 g ⁇ kg -1 d -1 .

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Abstract

本发明提供一种组合物及其抗菌应用，用于人体及人体所处环境中施用，能降低其存在的微生物的繁殖趋势，组合物包含：1.2％苹果酸、0.3％马尿酸、0.1％富马酸、0.1％甘氨酸和水。其中，所述组合物抑制大肠杆菌、金黄色葡萄球菌所使用的最低抑菌浓度比1.2％苹果酸、0.3％马尿酸、0.1％富马酸或0.1％甘氨酸单独抑制大肠杆菌、金黄色葡萄球菌所使用的最低抑菌浓度低2.5倍。

Description

一种组合物及其抗菌应用 技术领域
本发明涉及医药技术领域，尤其涉及一种组合物及其抗菌应用。
背景技术
宋代陈自明所著《妇人良方》中的“仙方活命饮”内使用穿山甲，全方功效包含清热解毒，消肿溃坚，活血止痛等疮疡肿毒初起，局部红肿热痛病症。明代李时珍的《本草纲目》记载穿山甲“除痰疟寒热，风痹强直疼痛，通经脉，消痛肿，排脓血，通窍杀虫。”其“附方”中提到“下痢里急”，穿山甲、蛤粉等分，同炒研末。从以上古代医书的记载中能够看到，穿山甲被用来治疗一些现代医学认为由细菌感染引起的疾病。郭毅等在《湖南中医学院学报》上报道穿山甲水煎液对大肠杆菌等11种细菌均具有抗菌作用，其中，水煎液的主要成分为鳞甲片。
但由于现代社会中穿山甲以处于极度濒危状态，8种穿山甲均已被列入《世界自然保护联盟》(IUCN)2014年濒危物种红色名录，2016年被列入《华盛顿公约》CITES附录Ⅰ级保护动物，禁止全球贸易。而我国是《濒危野生动植物物种国际贸易公约》(CITES)的缔约国。同时，2020年，《中国药典》将穿山甲排除入药。因此，本发明通过探究穿山甲鳞片中对菌群起抑制作用的成分或成分组合物，以此进行人工合成作为替代品，在保证替换了穿山甲成分的相关治疗方案不受影响的同时还能够保护濒危动物穿山甲。
在现有技术中，有机酸作为一种有机酸添加剂在各个领域中使用，其中柠檬酸作为使用频次最高的有机酸用于防腐和风味添加。公开号为CN108670897B的中国专利涉及到一种高效抑菌湿巾组合物及其制备方法。所述高效抑菌湿巾组合物的制备原料，以重量份计，包括乙醇1～6、丁二醇0.5～3、增溶剂0.2～0.6、薄荷醇0.01～0.02、香精0.1～0.12、茶叶提取物0.5～1.0、油橄榄叶提取物0.5～1.0、纳米银、马齿苋提取物0.5～1.0、柠檬酸0.1～0.2、柠檬酸钠0.05～0.15、苯氧乙醇0.01～0.05。该组合物的成分涉及了有机酸柠檬酸，并以此作为抑菌的成分，其中苯氧乙醇用于柠檬酸的助溶。然而，现存的有机酸多种多样，柠檬酸的抑菌效果在 其中无法达到最高的抑菌效率。
公开号为CN108904374A的中国专利涉及到一种口腔清洁剂，按照重量份数包括：茶提取物3-8份，柿涩1-3份，果糖1-2份，柠檬酸2-4份，香料1-3份。
一般来说漱口水或其他口腔清洁剂的PH值要在6.5-7.5范围内，该范围的PH值偏向中性，在中性的环境下，漱口水的使用不会破坏口腔内部的蛋白质，而且能起到很好的杀菌作用。由甘氨酸构成的甘氨酸缓冲液能够保持液体处于2.2-10.6范围内。绿脓杆菌和粘质沙雷菌是一种令免疫受损的机会性感染病原，多出现于伤口处。口腔清洁剂以对口腔内的绿脓杆菌和粘质沙雷菌形成繁殖抑制的作用防止绿脓杆菌和粘质沙雷菌进入呼吸道中对患者造成伤害。
在现有技术中，多种弱酸性的抑菌防腐效果得到证实，但针对对人体疾病影响最广泛和频次最高的大肠杆菌和金黄色葡萄球菌的抑制作用的有机酸的施用并未被发现。
本实验通过对具有良好抑菌效果的穿山甲鳞片的成分研究，探究穿山甲鳞片中的用于抑菌的代谢物组成，从而实现多组合弱酸替代穿山甲鳞片的抑菌作用。
此外，一方面由于对本领域技术人员的理解存在差异；另一方面由于申请人做出本发明时研究了大量文献和专利，但篇幅所限并未详细罗列所有的细节与内容，然而这绝非本发明不具备这些现有技术的特征，相反本发明已经具备现有技术的所有特征，而且申请人保留在背景技术中增加相关现有技术之权利。
发明内容
针对现有技术之不足，本发明提供了一种组合物。用于人体或人体所处的环境，能够降低所述环境中存在的微生物的繁殖趋势。组合物包含：苹果酸、马尿酸、富马酸、甘氨酸、琥珀酸、L-缬氨酸和柠檬酸中的一种或几种。
优选地，组合物中的成分包含：(1)苹果酸；(2)马尿酸；(3)以下任选地至少一组弱酸性成分：1)甘氨酸；2)琥珀酸和/或L-缬氨酸。
优选地，组合物中的成分包含：(1)苹果酸；(2)马尿酸；(3)以下任选地至少一组弱酸性成分：1)富马酸和/或甘氨酸；2)琥珀酸和/或L-缬氨 酸。
根据一种优选实施方式，由苹果酸、马尿酸、琥珀酸、L-缬氨酸构成的第一成分，并与由富马酸或琥珀酸构成的第二成分共同配比形成能够对微生物生长达到抑制效果的组合物。
本技术方案的优点：相较于单一的有机酸的施用，多重组合形成的有机酸组合能够以相较单一有机酸形成更好的抑菌效果(通过抑菌试验已证实)，并通过多种有机酸的组合形成不同的适用于食品、美妆、口腔清洁等作用于人体的消毒成分的风味，达到除臭清爽的目的。有机酸的形成和分解对人体无害且对环境同样无害，其抑菌杀菌的原理是以小分子形式进入细菌体内，并破坏细菌体内的碱性活性环境，从而抑制细菌活性。多种组合的有机酸的组合彼此间形成共价结构，并形成彼此增幅的抑菌效果，以较小剂量的组合物替代单性或多性随机组合的且需要大剂量添加的有机酸，从而减少食品添加剂过量摄入对人体带来的危害。
根据一种优选实施方式，作用于人体或环境的所述组合物包含苹果酸、马尿酸、甘氨酸和柠檬酸，其中，组合物基于苹果酸和柠檬酸的相互作用能够以缓冲酸性感官的方式增强用于作用于环境的果香成分。
根据一种优选实施方式，组合物至少包含苹果酸、马尿酸、甘氨酸和柠檬酸，其中，构成所述组合物的组分以非牛顿流体的形式施用于皮肤表面。
根据一种优选实施方式，所述组合物至少包含苹果酸、马尿酸、甘氨酸和富马酸，其中，构成所述组合物的组分以非牛顿流体的形式施用于皮肤表面。
本技术方案的优点：用于皮肤表面的修复、治疗或保护的药品、化妆品在涂抹过程中由于流体的流动性而在脸部无法达到稳定的挂接，但膏状的药品形态由于粘稠性不容易均匀涂抹。本发明采用非牛顿流体的组分形式，降低其流动性，并不改变粘稠度，从而保证组分在脸部及皮肤位置扒附的稳定性。
本发明涉及一种喷涂于人体表面或喷洒于人体所处环境的组合物，其包含以下物质：质量百分比为1.2％苹果酸、0.3％马尿酸、0.2％柠檬酸、0.1％甘氨酸和余量的水，所述组合物以通过抑制大肠杆菌、金黄色葡萄球菌繁殖的方式清洁人体或人体所处的环境，其中，
所述组合物抑制大肠杆菌、金黄色葡萄球菌所使用的最低抑菌浓度比1.2％苹果酸、0.3％马尿酸、0.2％柠檬酸、0.1％甘氨酸单独抑制大肠杆菌、金黄色葡萄球菌所使用的最低抑菌浓度低2.5倍。
本发明涉及包含质量百分比为1.2％苹果酸、0.3％马尿酸、0.2％柠檬酸、0.1％甘氨酸和余量的水的组合物在洗涤剂、抗菌药物或食品中的应用。
本发明涉及一种杀菌剂。杀菌剂包含组合式液体或气体颗粒，所述组合式液体或气体颗粒包含由高效抑菌的有机酸构成的颗粒核心和覆盖颗粒核心的由硅烷偶联剂中和的纳米级无机微孔形态的氧化锆-氧化锡复合体构成的用于保护和增加附着能力的外披膜，使得包裹有机酸的硅烷偶联剂中和的纳米级无机微孔形态的氧化锆-氧化锡复合体能够以气雾、气溶胶或小颗粒液体的方式分散于衣物、生活环境中，其中，所述有机酸被配置为：
质量百分比为1.2％苹果酸、0.3％马尿酸、0.2％柠檬酸、0.1％甘氨酸和余量的水。
所述有机酸抑制大肠杆菌、金黄色葡萄球菌所使用的最低抑菌浓度比1.2％苹果酸、0.3％马尿酸、0.2％柠檬酸或0.1％甘氨酸单独抑制大肠杆菌、金黄色葡萄球菌所使用的最低抑菌浓度低2.5倍，所述组合式液体或气体颗粒的制备方法如下：
称量：按照1：40比例称量以重量换算的硅烷偶联剂偶联和氧化锆氧化锡复合体，称量以体积换算的有机酸；
混合：将氧化锆氧化锡复合体分批次放入有机酸中，混匀，而后伴随搅拌动作缓慢倒入硅烷偶联剂偶联，搅拌至三相均匀，即获得浓缩后的组合式液体或气体颗粒。
本发明涉及一种组合物，其包含：质量百分比0.1％富马酸、1.2％苹果酸、0.3％马尿酸、0.1％甘氨酸和余量的水，其中，
所述组合物抑制大肠杆菌、金黄色葡萄球菌所使用的最低抑菌浓度比0.1％富马酸、1.2％苹果酸、0.3％马尿酸和0.1％甘氨酸单独抑制大肠杆菌、金黄色葡萄球菌所使用的最低抑菌浓度低2.5倍。
本发明涉及包含质量百分比0.1％富马酸、1.2％苹果酸、0.3％马尿酸、0.1％甘氨酸和余量的水的组合物在洗涤剂、抗菌药物或食品中的应用。
本发明涉及包含质量百分比0.1％富马酸、1.2％苹果酸、0.3％马尿酸、 0.1％甘氨酸和余量的水的组合物于抑制大肠杆菌、金属葡萄球菌、绿脓杆菌和粘质沙雷氏菌生长中的用途，其中，所述组合物能够对大肠杆菌、金属葡萄球菌、绿脓杆菌和粘质沙雷氏菌达到0.1C的抑菌效果。
本发明涉及一种杀菌剂。杀菌剂包含具有抑菌效果的第一组合物和以形成凝胶网络包裹所述第一组合物施用目标的第二组合物，所述第一组合物被配置为：质量百分比0.1％富马酸、1.2％苹果酸、0.3％马尿酸、0.1％甘氨酸和余量的水，作用于细菌胞内环境的富马酸、苹果酸、马尿酸、甘氨酸的分子直径能够小于大肠杆菌和金黄色葡萄球菌的胞膜通道直径，以使得所述第一组合物基于菌胞内部的碱性环境的改变而抑制大肠杆菌、金黄色葡萄球菌的活性，所述第一组合物抑制大肠杆菌、金黄色葡萄球菌所使用的最低抑菌浓度比单独添加0.1％富马酸、1.2％苹果酸、0.3％马尿酸或0.1％甘氨酸的杀菌剂抑制大肠杆菌、金黄色葡萄球菌所使用的最低抑菌浓度低2.5倍；
所述第二组合物被配置为：包含多糖和蛋白质的水胶体，其中，
所述第二组合物能够包裹所述第一组合物施用的目标，混合于所述第二组合物中的所述第一组合物能够基于对所述第一组合物施用的目标形成的压力进入所述目标内部，并在目标内部释放H +，破坏菌体内部碱性环境而抑制菌体活性。
本发明涉及一种抑制耐药细菌生长的组合物。所述组合物包含：512μg/ml苹果酸、32μg/ml富马酸和512μg/ml甘氨酸，其中，所述组合物能够抑制99％耐药鲍曼不动杆菌生长，并抑制90％耐药性金黄色葡萄球菌生长。
本发明涉及抑制耐药细菌生长的组合物在抑制甲氧西林耐药性菌株生长中的用途。
本发明涉及抑制耐药细菌生长的组合物在抑制碳青霉烯类抗生素耐药性菌株生长中的用途。
本发明涉及一种药物组合物。所述药物组合物包含512μg/ml苹果酸、32μg/ml富马酸、512μg/ml甘氨酸以及任选存在的药学上可接受的辅料。
本发明涉及一种能够对具有碳青霉烯类抗生素耐药性的鲍曼不动杆菌和具有甲氧西林耐药性的金黄色葡萄球菌产生抑制作用的组合物。所述组合物包含512μg/ml苹果酸、32μg/ml富马酸和512μg/ml甘氨酸。
本发明涉及一种能够对具有碳青霉烯类抗生素耐药性的鲍曼不动杆菌和具有甲氧西林耐药性的金黄色葡萄球菌产生抑制作用的组合物。所述组合物包含512μg/ml苹果酸、512μg/ml富马酸、512μg/ml甘氨酸和512μg/ml马尿酸。
本发明涉及一种用于细菌性肺部感染的药物组合物。所述药物组合物包含：苹果酸、马尿酸、富马酸、甘氨酸。
根据一种优选实施方式，所述用于细菌性肺部感染的药物组合物的剂量为0.5g·kg -1d -1～1.5g·kg -1d -1。
根据一种优选实施方式，组合物能够以协同作用的方式抑制大肠杆菌和金黄色葡萄球菌的分裂。
一种组合物，其能够以分散相的形式与摩擦剂构成口腔清洁剂的清洁成分，组合物用于对口腔内部的大肠杆菌和金黄色葡萄球菌的生长进行抑制，其中，组合物包含苹果酸、马尿酸、富马酸、甘氨酸、琥珀酸、L-缬氨酸和柠檬酸中的一种或几种。
一种组合物，其能够对人体皮肤表面或食品中的大肠杆菌和金黄色葡萄球菌的繁衍起到抑制作用，其中，组合物包含苹果酸、马尿酸、富马酸、甘氨酸、琥珀酸、L-缬氨酸和柠檬酸中的一种或几种。
一种组合物的抗菌应用，该组合物作为添加剂在洗涤剂或杀菌剂中施用，作为添加剂的所述组合物设置有用于释放H +的第一组合物和用于增加消杀效果和时间的第二组合物。第一组合物包含：苹果酸、马尿酸、富马酸、甘氨酸、琥珀酸、L-缬氨酸和柠檬酸中的一种或几种，第二组合物包含水胶体。其中，在作为添加剂的所述组合物施用时所述第一组合物介入所述第二组合物，并伴随所述第二组合物对洗涤剂或杀菌剂施用的目标携带的大肠杆菌或金黄色葡萄球菌的包裹而作用于大肠杆菌或金黄色葡萄球菌的菌体内部。
一种组合物的抗菌应用，其特征在于，用于细菌性肺部感染中的细菌的生长抑制药物，所述药物的主要成分包含：苹果酸、马尿酸、富马酸、甘氨酸、琥珀酸、L-缬氨酸和柠檬酸中的一种或几种。
说明书附图
图1为本发明中不同浓度的代谢物组合对大肠杆菌、金属葡萄球菌、绿 脓杆菌和粘质沙雷氏菌的生长情况的影响结果示意图；
图2为高浓度组分的不同组合分别对鲍曼不动杆菌和金黄色葡萄球菌的抑制率的结果示意图；
图3为二、三和四组分联用组合对耐药的鲍曼不动杆菌的时间杀菌曲线图；
图4为二、三和四组分联用组合联用组合对耐甲氧西林金黄色葡萄球菌的时间杀菌曲线图；
图5为低、中、高剂量代谢物组合和环丙沙星对于大肠杆菌引起的小鼠肺部感染模型的肺部载菌量的影响示意图；
图6为低、中、高剂量的代谢组合物和环丙沙星治疗后的小鼠肺部组织HE染色图。
具体实施方式
下面结合附图进行详细说明。
本发明设计一种抑菌组合物，其能够对以大肠杆菌和金黄色葡萄球菌为代表的微生物实现最有效果的抑制作用。
用于抑菌的有机酸包含富马酸(Fumaric acid)、琥珀酸(Succinic acid)、L-缬氨酸(L-Valine)、苹果酸(Malic acid)、柠檬酸(Citric acid)、甘氨酸(Glycine)和马尿酸(Hippuric acid)。其比例与穿山甲鳞片中含量一致，其中，在总提取液(CV)中，富马酸占比0.1％、琥珀酸占比0.4％、L-缬氨酸占比1.3％、苹果酸占比1.2％、柠檬酸占比0.2％、甘氨酸占比0.1％和马尿酸占比0.3％。优选的，上述比例是可以调整的，也是有效的。
本文中涉及的微生物能够包含革兰氏阴性菌、革兰氏阳性菌，或包含以金黄色葡萄球菌为致病葡萄球菌的代表，以大肠杆菌为代表的条件致病菌或其他致病细菌，如结核杆菌。
本发明中用于实验和构成组合物成分的有机酸均为人工合成的有机酸。
通过该类组合物悬殊性含量配比，从而达到相较同体积的单一或少组合物的更优抑菌的效果。
实施例1
基于最小抑菌浓度法(MIC)进行抑菌试验，分别将上述抗菌代谢物用于大肠杆菌(E.coli；Escherichia coli)和金黄色葡萄球菌(S.aureus； Staphylococcus aureus)、绿脓杆菌(P.aeruginosa；Pseudomonas aeruginosa)和粘质沙雷菌(S.marcescens；Serratia marcescens)的最小抑菌浓度(MIC；Minimum Inhibitory Concentration)检测。
(1)实验材料：
1)培养基
采用溶菌肉汤(LB；Lysogeny Broth)培养基，含10g/L蛋白胨，5g/L酵母提取物和10g/L氯化钠。
2)抗菌药物：
包含富马酸、琥珀酸、L-缬氨酸、苹果酸、柠檬酸、甘氨酸和马尿酸中的一种或几种构成的全部组合物。
(2)抑菌试验步骤如下：
1)菌悬液制备
将保存的代表革兰氏阴性菌的大肠杆菌和代表革兰氏阳性菌的金黄色葡萄球菌同时复苏。用接种环在已分纯的待测菌平板上，挑取单个直径约1mm的菌落，接种于2ml LB肉汤中，于37℃的生化培养箱中进行培养。增菌后的对数生长期菌液用LB肉汤校正浓度至0.5麦氏比浊标准(即625nm处吸光度为0.08～0.10)，约含1×10 8～2×10 8CFU·ml -1。
2)抗菌药物制备
采用二倍稀释法制备浓度为4C、2C、C、0.5C、0.25C、0.125C、0.0625C、0.03125C的组合抗菌药物，取无菌试管8支依次编号，在2-8支试管中加入1ml无菌水。在第一个试管中配制2ml 4C的抗菌药物，取1ml第一支试管中的溶液加入第二支试管，混匀后，再取1ml第二支试管中的溶液加入到第三支试管，依次稀释。
3)MIC测定
在96孔板的第1列加入200μl LB肉汤培养基作阴性对照，第2-10列中加入180μl制备好的菌悬液至终浓度为1×10 5CFU·ml -1。第2列加入20μl无菌水作为阳性对照组，第3～10列分别加入20μl药物浓度终浓度依次为0.4、0.2、0.1、0.05、0.025、0.0125、0.00625和0.003125C。将分别接种好的药敏板置于37℃温箱中培养24h，通过观察LB肉汤培养基的浊度并检测OD值来检测MIC值，实验重复3次。
得到结果如表1中各个代谢物对大肠杆菌和金黄色葡萄菌的最小抑制浓度，独立存在的集中抗菌代谢物汇总，对于大肠杆菌和金黄色葡萄球菌抑制效果最好的是苹果酸。
Figure PCTCN2022124947-appb-000001
表1
为了验证苹果酸及其组合物形成的最优效果，本实验进一步将苹果酸与其他代谢物作为组合物进行抑菌试验，得到以MIC值为代表的结果如表2所示。
Figure PCTCN2022124947-appb-000002
表2
实验结果显示，添加了苹果酸的双成分组合物对大肠杆菌和金黄色葡萄球菌的MIC值变小，表明其对大肠杆菌和金黄色葡萄球菌具有更高的抑制效果。再进一步，进行三种组合物的随机分配，并进行抑菌试验，如表3所示。
Figure PCTCN2022124947-appb-000003
Figure PCTCN2022124947-appb-000004
表3
苹果酸和富马酸的组合物在与L-缬氨酸或柠檬酸组合时抑菌效果回弹变弱，同样的，苹果酸和L-缬氨酸在与甘氨酸或马尿酸组合时结果相同，对大肠杆菌和金黄色葡萄球菌的抑制效果减弱，MIC值回升至0.4C。苹果酸、马尿酸和柠檬酸形成的组合物对大肠杆菌的抑制效果达到最优，MIC值为0.1C。
本实验还对选择苹果酸作为主要成分，通过分配其他代谢物与苹果酸构成四种组合物进行抑菌试验，结果如表4所示。
Figure PCTCN2022124947-appb-000005
Figure PCTCN2022124947-appb-000006
表4
结果显示，苹果酸、富马酸、甘氨酸和马尿酸的组合物以及苹果酸、柠檬酸、甘氨酸和马尿酸的组合物能够形成MIC低至0.1C的抑菌效果。
本实验还对选择苹果酸作为主要成分，通过分配其他代谢物与苹果酸构成五种组合物进行抑菌试验，结果如表5所示。
Figure PCTCN2022124947-appb-000007
Figure PCTCN2022124947-appb-000008
表5
结果显示，苹果酸、L-缬氨酸、柠檬酸、甘氨酸、马尿酸；苹果酸、富马酸、琥珀酸、L-缬氨酸、马尿酸；苹果酸、富马酸、L-缬氨酸、甘氨酸、马尿酸三种组合物能够对大肠杆菌形成MIC值0.1C的抑菌效果。而组合物苹果酸、琥珀酸、L-缬氨酸、甘氨酸、马尿酸；苹果酸、富马酸、L-缬氨酸、柠檬酸、马尿酸；苹果酸、富马酸、柠檬酸、甘氨酸、马尿酸；苹果酸、琥珀酸、L-缬氨酸、柠檬酸、马尿酸；苹果酸、琥珀酸、柠檬酸、甘氨酸、马尿酸中任一组能够对大肠杆菌和金黄色葡萄球菌形成MIC值0.1C的抑菌效果。相较于现有技术中使用单一有机酸或两项有机酸作为添加剂，其抑菌效果达不到四种以上有机酸组合形成的抑菌添加剂。
本实验还对选择苹果酸作为主要成分，通过分配其他代谢物与苹果酸构成六种组合物、七种代谢物混合进行抑菌试验，结果如表6所示。
Figure PCTCN2022124947-appb-000009
表6
结果显示，即使是六种及以上的代谢物混合，其对金黄色葡萄球菌和大肠杆菌的抑菌效果能够达到MIC值0.1C。
进一步，以大肠杆菌、金属葡萄球菌、绿脓杆菌和粘质沙雷菌为例，对包含苹果酸、马尿酸、富马酸和甘氨酸的代谢物组合进行试验，结果如表7所示：
Figure PCTCN2022124947-appb-000010
表7
结果显示，由苹果酸、马尿酸、富马酸和甘氨酸构成的有机酸代谢物组合物对大肠杆菌和金黄色葡萄球菌的抑菌效果达到MIC值0.1C，对绿脓杆菌和粘质沙雷菌的抑菌效果达到MIC值0.2C。由苹果酸、马尿酸、富马酸和甘氨酸构成的有机酸代谢物组合物对以大肠杆菌、金属葡萄球菌、绿脓杆菌和粘质沙雷菌为代表的细菌，尤其是致病菌，具有对其生长的抑制作用。
粘质沙雷菌为细菌最小者，属革兰氏阴性杆菌，为条件致病菌。
绿脓杆菌是一种革兰氏阴性菌，为机会性感染细菌。
大肠杆菌、金属葡萄球菌、绿脓杆菌和粘质沙雷菌广泛分布于自然界中，其能够通过人体口鼻等位置进入人体，在一定条件或环境状态下引起人体产生炎症等致病反应。因此，本实验选用上述四种菌种作为抑菌试验的试验对象。
基于上述实验结果，苹果酸、甘氨酸和马尿酸构成的组合物能够与柠檬酸或富马酸形成对金黄色葡萄球菌和大肠杆菌的抑菌效果达到MIC值0.1C的效果。
上述用于实验的组合物中的配比能够为富马酸占比0.1％、琥珀酸占比0.4％、L-缬氨酸占比1.3％、苹果酸占比1.2％、柠檬酸占比0.2％、甘氨酸占比0.1％和马尿酸占比0.3％，以上述比例进行抗菌组合物配制。
优选地，用于降低人体体表或人体所处环境中存在的微生物的繁殖趋势的组合物包含：0.125％～0.482％苹果酸、0.135％～0.422％L-缬氨酸、0.021％～0.081％柠檬酸、0.01％～0.04％琥珀酸、0.031％～0.121％马尿酸、0.001％～0.041％甘氨酸和0.01％～0.041％富马酸中的一种或几种。
优选地，所述组合物中各组分比例能够为：苹果酸在总组分中占比1％～30％、L-缬氨酸在总组分中占比0.1％～20％、柠檬酸在总组分中占比0.1％～20％、琥珀酸在总组分中占比0.1％～20％、马尿酸在总组分中占比0.1％～20％、甘氨酸在总组分中占比0.1％～20％和富马酸在总组分中占比0.1％～20％。
优选地，所述组合物中各组分比例能够为：苹果酸在总组分中占比10％～40％、L-缬氨酸在总组分中占比0.01％～10％、柠檬酸在总组分中占比0.01％～10％、琥珀酸在总组分中占比0.01％～20％、马尿酸在总组分中占比0.01％～20％、甘氨酸在总组分中占比0.01％～20％和富马酸在总组分中占比0.01％～10％。
优选地，所述苹果酸能够在总组分中按重量计在约0.1％至约20％、约1％至约10％、约3％至约8％、约6％至约12％、约15％至约18％、约17％至约20％、20％至60％的范围内，或按重量计为约1％、约2％、约3％、约4％、约5％、约6％、约7％、约8％、约9％、约10％、约15％、约20％、约30％或约40％，包括其间的所有范围和子范围。
优选地，所述L-缬氨酸能够在总组分中按重量计在约0.01％至约1％、约1％至约10％、约3％至约8％、约6％至约12％、约15％至约18％、约17％至约20％的范围内，或按重量计为约1％、约2％、约3％、约4％、约5％、约6％、约7％、约8％、约9％、约10％、约15％、约20％、约30％或约40％，包括其间的所有范围和子范围。
优选地，所述柠檬酸能够在总组分中按重量计在约0.01％至约2％、约1％至约10％、约3％至约8％、约6％至约12％、约15％至约18％、约17％至约20％的范围内，或按重量计为约1％、约2％、约3％、约4％、约5％、约6％、约7％、约8％、约9％、约10％、约15％、约20％、约30％或约40％，包括其间的所有范围和子范围。
优选地，所述琥珀酸能够在总组分中按重量计在约0.1％至约20％、约 1％至约10％、约3％至约8％、约6％至约12％、约15％至约18％、约17％至约20％的范围内，或按重量计为约1％、约2％、约3％、约4％、约5％、约6％、约7％、约8％、约9％、约10％、约15％、约20％、约30％或约40％，包括其间的所有范围和子范围。
优选地，所述马尿酸能够在总组分中按重量计在约0.1％至约20％、约1％至约10％、约3％至约8％、约6％至约12％、约15％至约18％、约17％至约20％、20％至60％的范围内，或按重量计为约1％、约2％、约3％、约4％、约5％、约6％、约7％、约8％、约9％、约10％、约15％、约20％、约30％或约40％，包括其间的所有范围和子范围。
优选地，所述甘氨酸能够在总组分中按重量计在约0.1％至约2％、约1％至约10％、约3％至约8％、约6％至约12％、约15％至约18％、约17％至约20％的范围内，或按重量计为约1％、约2％、约3％、约4％、约5％、约6％、约7％、约8％、约9％、约10％、约15％、约20％、约30％或约40％，包括其间的所有范围和子范围。
优选地，所述富马酸能够在总组分中按重量计在约0.01％至约20％、约1％至约10％、约3％至约8％、约6％至约12％、约15％至约18％、约17％至约20％的范围内，或按重量计为约1％、约2％、约3％、约4％、约5％、约6％、约7％、约8％、约9％、约10％、约15％、约20％、约30％或约40％，包括其间的所有范围和子范围。
优选地，苹果酸、L-缬氨酸、柠檬酸、琥珀酸、马尿酸、甘氨酸和富马酸的组合范围能够包含但不限于上述的比例和组合范围。
对于大肠杆菌具有MIC值达到0.1C的抑制效果的组合物以苹果酸、马尿酸和柠檬酸的组合物作为代表，而同时对大肠杆菌和金黄色葡萄球菌具有MIC值达到0.1C的抑制效果的组合物以苹果酸、富马酸、甘氨酸、马尿酸；苹果酸、柠檬酸、甘氨酸、马尿酸为代表。由于上述形成组合物的成分均为弱酸性成分，且均能够作为食品添加剂被人体吸收，因此，作为对人体无害的成分，上述多组组合物能够应用于多种领域。现有技术中，使用有机酸的方法和认知为：任一有机酸均具有抑菌作用，通过法律允许的范围内大剂量的在食物或其他与人体接触的消毒液体中添加并进行抑菌即可。然而，有机酸作为添加剂在大量使用时会在身体内产生转化产物，少剂量依靠代谢，但 大剂量则无法保证全部产物能够及时的代谢出体外，因此大剂量的添加剂在一定时间内会对人体身体造成危害。本发明通过对有效抑菌的有机酸进行抑菌配比，得到最优的抑菌组合物，能够通过增加可食用有机酸的种类来减少可食用有机酸的添加量，从而帮助食物或其他在保证防腐效果的同时形成对人体更健康的影响。
实施例2
本实施例是对实施例1的进一步改进，重复的内容不再赘述。
以目前用于慢性咽炎治疗的利咽片为例。针对细菌感染产生的慢性咽炎，利咽片能够对该病症产生较好的作用。利咽片成分包含穿山甲(制)、土鳖虫、僵蚕、牡蛎(煅)、玄参，其成分中的穿山甲(制)由于取自濒危生物，该成分为禁用药品，导致利咽片无法被作为处方药或非处方药为患者治疗。本发明通过探究穿山甲鳞片中对菌群抑制，尤其是大肠杆菌和金黄色葡萄球菌的抑制作用进行探究，发现对大肠杆菌和金黄色葡萄球菌具有有效抑制作用的一组或多组组合物。药物的主要成分包含：苹果酸、马尿酸、富马酸、甘氨酸、琥珀酸、L-缬氨酸和柠檬酸中的一种或几种。在进行利咽片的穿山甲成分替换时，一方面替换成分能够采用相似成分的生物组织提取物，另一方面替换成分还能够是通过人工合成有效抑菌的代谢物替代品成分。优选地，替换成分使用人工合成的化合物时，其能够为本实验中设计的对以大肠杆菌为代表的革兰氏阴性菌和以金黄色葡萄球菌为代表的革兰氏阳性菌抑制效果最优之一的组合物：苹果酸、富马酸、琥珀酸、L-缬氨酸、柠檬酸和甘氨酸。上述有机酸的添加还能够为药片带来果味等受儿童欢迎的口味，从而增加婴幼儿服药的积极性。
实施例3
本实施例是对实施例1或实施例2的进一步改进，重复的内容不再赘述。
组合物还是用于各种食品中作为添加剂组合物，有效抑制食品中的大肠杆菌和金黄色葡萄球菌。例如，在一些天然果汁中添加，即通过苹果酸和柠檬酸的配比增加天然风味，又配合果汁在真空或密封包装通过抑制大肠杆菌和金黄色葡萄球菌的生长而实现防腐效果。添加剂的主要成分包含：苹果酸、马尿酸、富马酸、甘氨酸、琥珀酸、L-缬氨酸和柠檬酸中的一种或几种。苹果酸和柠檬酸分别存在或组合作用会形成具有水果风味的添加剂。
实施例4
本实施例是对实施例1、实施例2或实施例3的进一步改进，重复的内容不再赘述。
组合物还能够用于家庭或对一般生活条件下的细菌消杀。例如，在家居生活中，需要对环境进行抑菌细菌维护或对衣物进行抑菌清洗，尤其是对人体有害的金黄色葡萄球菌。酒精或84消毒液的消杀对人体同样具有损伤，且不适合有孕妇或儿童的家庭使用。本发明能够基于该弱酸性成分的组合物，并配合其他无危害消杀细菌的成分形成适用于有儿童或孕妇的家庭的消杀细菌的液体试剂。
有机酸构成的组合物能够作为添加剂在洗涤剂或杀菌剂中施用。作为添加剂的组合物用于衣物或环境抑菌除臭。组合物设置有包含作为PH调节剂的第一组合物和用于增加消杀效果和时间的第二组合物。第一组合物包含两种组合中的任意一种：苹果酸、甘氨酸、马尿酸、柠檬酸；苹果酸、甘氨酸、马尿酸、富马酸。第二组合物包含水胶体。
包含多糖和蛋白质的水胶体形成凝胶网络。在由凝胶网络包裹洗涤剂或杀菌剂施用的目标携带的大肠杆菌或金黄色葡萄球菌时，存在于水胶体中的第一组合物基于凝胶网络对菌体的压力而自菌体进入菌体内部，第一组合物和第二组合物共同作用形成具有协同作用的有机酸，在菌体内部释放H +，破坏菌体内部碱性环境，从而抑制菌体活性。第一组合物介入水胶体，并伴随水胶体对洗涤剂或杀菌剂施用的目标携带的大肠杆菌或金黄色葡萄球菌的包裹而作用于大肠杆菌或金黄色葡萄球菌的菌体内部。
用于作用于细菌胞内环境的有机酸的分子直径能够小于大肠杆菌和金黄色葡萄球菌的胞膜通道直径以使有机酸分子能够自胞膜通道进入菌胞内部并破坏菌胞内部的碱性环境从而抑制菌胞活性。
通过苹果酸、甘氨酸和马尿酸构成的第一组合物与柠檬酸或富马酸构成的第二组合物的协同作用，实现大肠杆菌和金黄色葡萄球菌的共同抑制作用。
实施例5
本实施例是对实施例1、实施例2、实施例3或实施例4的进一步改进，重复的内容不再赘述。
本发明设计一种组合物，该组合物用于以喷洒、雾化或其他形成小颗粒气体或液体的方式扩散至目标表面并消杀和抑制目标表面的大肠杆菌和金黄色葡萄球菌。
组合物由组合式液体或气体颗粒构成。上述液体或气体颗粒包含由高效抑菌的有机酸构成的颗粒核心和覆盖颗粒核心的由硅烷偶联剂中和的纳米级无机微孔形态的氧化锆-氧化锡复合体构成的用于保护和增加附着能力的外披膜。
通过将包裹有机酸的硅烷偶联剂中和的纳米级无机微孔形态的氧化锆-氧化锡复合体以气雾、气溶胶或小颗粒液体的方式分散于衣物、生活环境中，在包裹有机酸的硅烷偶联剂中和的纳米级无机微孔形态的氧化锆-氧化锡复合体触碰目标表面的大肠杆菌和金黄色葡萄球菌时，外皮膜基于压力释放有机酸并允许有机酸通过细菌表面的胞膜进入细菌体内，从而抑制细菌活性。氧化锆-氧化锡复合体形成的纳米级无机微孔能够允许有机酸分子进出，并限制大体积颗粒对该颗粒的分解和附着的阻碍。氧化锆-氧化锡复合体能够有效的在构成以气溶胶或液体、气体形态存在的颗粒的外披膜时保持外披膜的硬度和防纳米微孔塌陷的韧度。
优选地，硅烷偶联剂与纳米级无机微孔形态的氧化锆-氧化锡复合体的比例在1:40～1:120。纳米级无机微孔形态氧化锆-氧化锡复合体与有机酸的比例在1:1～1:10之间。
由硅烷偶联剂偶联的有机体-无机体构成的微颗粒能够以直径至少小于10μm的状态向目标表面移动。上述微颗粒在用于稀释或均匀液相的水相中具有优良的分散稳定性，携带有机酸在目标表面的高附着率以及由于外皮膜的包裹而降低有机酸核心的高挥发性能。利用低成本的且能够稳定偶联内部的有机层与外部的无机层的中间相，在不损害有机层氢离子的游离的情况下，增加与有机层偶联且不发生其他化学反应的无机层，通过无机层的性质克服了有机层在目标表面附着力差、无作用且易挥发的问题。优选地，硅烷偶联剂偶联能够为水性硅烷偶联剂偶联。
上述组合物的配制方法如下：
(1)称量：按照比例称量以重量换算的硅烷偶联剂偶联和氧化锆氧化锡复合体(其能够以溶胶形式存在)，称量以体积换算的有机酸组合物；
(2)混合：将氧化锆氧化锡复合体分批次放入有机酸中，混匀，而后伴随搅拌动作缓慢倒入硅烷偶联剂偶联，搅拌至三相均匀，即获得浓缩后的组合物。
浓缩后的组合物在使用前能够添加水进行浓度稀释，而后通过气雾机、喷壶等设备向环境或衣物等需要消毒的目标表面喷洒。
上述颗粒核心的有机酸能够与上述实施例中涉及的能够对大肠杆菌和金黄色葡萄球菌的抑菌效果达到MIC为0.1C的有机酸组合物。由本发明中涉及的由外皮膜包裹的有机酸组合在水中具有良好的稳定性，并对大肠杆菌和金黄色葡萄球菌具有高效的抑制效果。
实施例6
本实施例是对实施例1、实施例2、实施例3、实施例4或实施例5的进一步改进，重复的内容不再赘述。
针对上述能够持久附着于表面并作用于细菌的有机酸组合物，本发明能够设计一种具有苹果酸、马尿酸、富马酸、甘氨酸、琥珀酸、L-缬氨酸和柠檬酸中的一种或几种的抑菌药膏或喷雾，其能够作用于面部、手臂、重要器官等皮肤表面或黏膜。有机酸组合成分对以大肠杆菌和金色葡萄球菌为代表的革兰氏阴性菌和革兰氏阳性菌等多种致病性皮肤菌的繁衍具有明显的抑菌作用。
优选地，所述抑菌药膏，包括中药膏、中药粉、贻贝粘蛋白和包含苹果酸、马尿酸、富马酸、甘氨酸、琥珀酸、L-缬氨酸和柠檬酸中的一种或几种的有机酸组合物。
优选地，所述抑菌喷雾，包含戊二醇、1,3丙二醇和含苹果酸、马尿酸、富马酸、甘氨酸、琥珀酸、L-缬氨酸和柠檬酸中的一种或几种的有机酸组合物。
实施例7
如图1中a、b、c、d四个散点图所示，苹果酸、马尿酸、富马酸和甘氨酸构成的组合物对大肠杆菌(E.coli)、金属葡萄球菌(S.aureus)、绿脓杆菌(P.aeruginosa)和粘质沙雷氏菌(S.marcescens)的生长的影响。图1中的红色箭头指代细菌的MIC值。该结果表示当苹果酸、马尿酸、富马酸和甘氨酸构成的组合物对大肠杆菌、金属葡萄球菌、绿脓杆菌和粘质沙雷氏 菌具有很强的抑菌效果。
图1中e、f、g、h四个折线图显示苹果酸、马尿酸、富马酸和甘氨酸构成的组合物使用MIC浓度对大肠杆菌、金属葡萄球菌、绿脓杆菌和粘质沙雷氏菌在24h内的OD值变化。图1中的i图为苹果酸、马尿酸、富马酸和甘氨酸构成的组合物在MIC，24h下对大肠杆菌和金色葡萄球菌的SEM图。
图1中的e、f、g、h四个折线图显示，在苹果酸、马尿酸、富马酸和甘氨酸构成的组合物施用的12h内，相对于未施用本组合物的对照组，大肠杆菌、金属葡萄球菌、绿脓杆菌和粘质沙雷氏菌的生长、扩增受到了抑制，其OD值保持不变。
通过上述实验证明了苹果酸、马尿酸、富马酸和甘氨酸构成的组合物，尤其是0.1％富马酸、1.2％苹果酸、0.3％马尿酸、0.1％甘氨酸构成的组合物能够通过抑制大肠杆菌、金属葡萄球菌、绿脓杆菌和粘质沙雷氏菌生长而实现环境中微生物菌群的数量控制，从而达到抑菌消毒的作用。
实施例8
本发明还进行了多组分化合物最优抑菌组合筛选及其时间杀菌曲线的研究。
疾病多元化出现的趋势，抗菌药物的广泛和多频率的使用，造成了细菌耐药性的提升。耐药细菌感染造成的重病、伤病不愈已经成为全球发展的趋势，并对公共健康构成重要威胁，因此，寻找对抗耐药细菌的药物和用药方案成为医学研发重点。
本发明采用两种耐药细菌进行抑菌实验，而获得了本发明中的对耐药细菌具有良好抑制作用的组合物。耐药细菌采用鲍曼不动杆菌(A cinetobacter baumanni)和金黄色葡萄球菌(Staphylococcus aureus)。鲍曼不动杆菌具有碳青霉烯类抗生素耐药性，其微生物菌种编号为bio-53272。金黄色葡萄球菌具有甲氧西林耐药性，其微生物菌种编号为ATCC BAA-1556。
本发明测定两种耐药细菌的单组分MIC，以寻找最优药物组合及其最优浓度。
具体地，测试方法包含细菌MIC测定、组合物成分筛选、浓度筛选以及多联筛选四个实验过程。
根据美国临床和实验室标准化协会的抗微生物药物敏感性试验执行标 准(CLSI-M100)进行两种耐药细菌的单组分MIC测定，具体步骤如下：
1.于当日16：30进行菌种活化，50μl菌液加入至含有2ml MHB培养基的离心管中，置于摇床，于37℃/1751pm条件下振荡培养过夜；
2.于次日10：30进行菌株复培：活化菌液，吸取50μl菌液加至2ml MHB中，振荡培养4-5h；
3.于次日13：00加样：二倍稀释法稀释待测组分，浓度为10mg/ml，取10.24μl加入到含89.76μl MHB的B2-F2孔内，此时该孔组分的浓度为1024μg/ml，B2-F2梯度稀释至B12-F12孔；
4.于次日15：30加菌液：吸取离心管中稀释的菌悬液加至96孔板，使用酶标仪测定OD值，根据OD值进一步稀释至10 9CFΜ/ml(OD≈0.2)，吸取20μl的10 9CFΜ/ml的菌悬液至20ml MHB中，即可得到10 6CFΜ/ml工作菌悬液，吸取50μl工作菌悬液至Bl-F12及G7-G12孔位；
5.将待测96孔板振荡3-4min，封口后放入生化培养箱37℃培养过夜；
6.于第三日9：00进行OD读数：从培养箱中取出96孔板，基于浑浊度确定MIC值，再使用酶标仪测量孔板内菌液在595nm的OD值。
结果如表8所示，表8为四组分对两种细菌的最小抑菌浓度(MIC)。根据表8所示，各组分MIC值均大于512μg/ml，故选择各组分均为512μg/ml作为最高测试浓度，将各组分进行组合联用，测试各组合对两种细菌的抑制效果，以筛选最优组分组合。
Figure PCTCN2022124947-appb-000011
表8
根据单组分MIC的测试结果，进行多组分联用最优组合筛选。具体步骤如下：
1.于当日16：30进行菌种活化：50μl菌液加入至含有2ml MHB培养基的离心管中，置于摇床，于37℃/175rpm条件下振荡培养过夜；
2.于次日10：30进行菌株复培：将活化菌液，吸取50μl菌液加至2ml MHB中，振荡培养4-5h。
3.于次日13：00加样：根据选定组合中所需组分浓度进行加液；
4.于次日15：30加菌液：吸取离心管中稀释的菌悬液加至96孔板，然后使用酶标仪测定OD值，根据OD值进一步稀释至10 9CFΜ/ml(OD≈0.2)。后吸取20μl 10 9CFΜ/ml菌悬液至20ml MHB中，即可得到10 6CFΜ/ml工作菌悬液，吸取50μl工作菌悬液至B1-F12及G7-G12孔位；
5.将待测96孔板振荡3-4min，封口后放入生化培养箱37℃培养过夜；
6.于第三日9：00进行OD读数：从培养箱中取出96孔板，根据浑浊度确定MIC值，再使用酶标仪测量菌液在595nm的OD值。
表9示出高浓度(512μg/ml)时两组分联用组合分别对鲍曼不动杆菌和金黄色葡萄球菌的抑制率，其中表中高亮即为筛选出的最优组合。
结果显示，512μg/ml富马酸和512μg/ml甘氨酸的构成的两联组合物能够对耐药性金黄色葡萄球菌产生最优的抑菌效果。对于耐药性鲍曼不动杆菌，各组分浓度均为512μg/ml时，二组分联用组合中效果最好的是PF-13组合，但其未能达到完全抑制。512μg/ml苹果酸和512μg/ml甘氨酸的构成的两联组合物能够对耐药性鲍曼不动杆菌产生最优的抑菌效果。对于耐药性金黄色葡萄球菌，各组分浓度均为512μg/ml时，所有组合物均无法达到完全抑制的效果，其中，效果较好的是二组分联用组合中的PF-23组合(抑制约70％细菌生长)。
Figure PCTCN2022124947-appb-000012
表9
根据多组分最优组合筛选结果，对抑制率高于90％的组合进行分级抑制浓度(FIC)的测试，以期得到各组分的最优浓度。具体步骤如下：
1.于当日16：30进行菌种活化：50μl菌液加入至含有2ml MHB培养基的离心管中，置于摇床，于37℃/175rpm条件下振荡培养过夜；
2.于次日10：30进行菌株复培：活化菌液，吸取50μl菌液加至2ml MHB中，振荡培养4-5h；
3.于次日13：00加样：使用深孔板配制4096-256μg/ml的各组分二倍稀释梯度浓度溶液，96孔板的测试孔位中加入12.5μl的各组分不同浓度溶液，若某组分的测试浓度为0则以MHB代替；
4.于次日15：30加菌液：吸取离心管中稀释的菌悬液加至96孔板，使用酶标仪测定OD值，根据OD值进一步稀释至10 9CFΜ/ml(OD≈0.2)，后吸取20μl 10 9CFΜ/ml菌悬液至20ml MHB中，即可得到10 6CFΜ/ml工作菌悬液，吸取50μl工作菌悬液加样96孔板中的待测孔位；
5.将待测96孔板振荡3-4min，封口后放入生化培养箱37℃培养过夜；
6.于第三日9：00进行OD读数：从培养箱中取出96孔板，根据浑浊度确定MIC值，再使用酶标仪测量菌液在595nm的OD值。
表10示出高浓度(512μg/ml)时三、四组分联用组合分别对鲍曼不动杆菌和金黄色葡萄球菌的抑制率，其中表中高亮即为筛选出的最优组合。
结果显示，由512μg/ml苹果酸、512μg/ml甘氨酸和512μg/ml富马酸构成的三联组合物能够对耐药性鲍曼不动杆菌和耐药性金黄色葡萄球菌产生三联组合物中最优的抑菌效果。512μg/ml苹果酸、512μg/ml富马酸、512μg/ml甘氨酸和512μg/ml马尿酸构成的四联组合物能够对耐药性鲍曼不动杆菌和耐药性金黄色葡萄球菌分别产生100％和94.18％的抑菌效果。
对于耐药性鲍曼不动杆菌，三组分联用中PF-123可完全抑制，PF-134可抑制约90％细菌生长。该结果也佐证PF-1、PF-3的协同作用是其抑菌效果的重要组成部分。
对于耐药性金黄色葡萄球菌，三组分联用的PF-123组合抑制约90％细菌生长。
Figure PCTCN2022124947-appb-000013
表10
根据多组分最优浓度组合测试结果，于二、三、四组分联用中挑选最优浓度组合，进行时间杀菌曲线测试4，步骤如下：
1.于当日16：30进行菌种活化：50μl菌液加入至含有2ml MHB培养基的离心管中，置于摇床，于37℃/175rpm条件下振荡培养过夜。
2.于次日6：30进行菌株复培：活化菌液，吸取50μl菌液加至2ml MHB中，振荡培养4-5h；
3.于次日9：00加样：将二、三、四组分联用组合配制为700μl所需浓度的溶液，分别加50μl至96孔板的E1-E12、Dl-D12、C1-C12孔位；F1-F12孔位中加入50μl MHB；
4.于次日10：00加菌液：吸取离心管中稀释的菌悬液加至96孔板，使用酶标仪测定OD值，根据OD值进一步稀释至10 9CFΜ/ml(OD>0.2)，后吸取20μl 10 9CFΜ/ml菌悬液至20ml MHB中，即可得到10 6CFΜ/ml工作菌悬液，吸取50μl工作菌悬液加样96孔板中的待测孔位；
5.将待测96孔板振荡3-4min，取F1孔进行10倍浓度梯度稀释并于LB琼脂平板上测其细菌浓度，封口后于生化培养箱中进行37℃培养，分别培养0.5、1、2、3、4、5、6、7、12、24h后将96孔板取出，分别取C2-F2、C3-F3.....C11-F1l孔位进行10倍浓度梯度稀释并测其实时细菌浓度，LB琼脂平板的培养物于生化培养箱中37℃培养过夜后进行菌落计数；
6.根据各时间点的菌落计数绘制时间杀菌曲线。
PF-1为苹果酸。PF-2为富马酸。PF-3为甘氨酸。PF-4为马尿酸。
根据筛选出的有效组分组合，进行各组分梯度浓度联用测试，结果中有 抑制效果的浓度组合如下表11所示，其中，高亮即为筛选出的对耐药金黄色葡萄球菌最优浓度组合以及对耐药鲍曼不动杆菌最优浓度组合。
对于耐药性鲍曼不动杆菌，二组分联用时，由于PF-1(512μg/ml)和PF-3(512μg/ml)未完全抑制，且仅PF-13组合达到约90％抑制率，即为二组分联用最优浓度组合；三组分联用时，PF-1(512μg/ml)、PF-2(32μg/ml)和PF-3(512μg/ml)可完全抑制，此即为最优浓度组合(完全抑制且药物浓度最低)；四组分联用时，PF-4的浓度无影响，可于三组分最优浓度组合任意添加PF-4浓度，均可达到完全抑制的效果。
对于耐药性金黄色葡萄球菌，二组分联用时，由于PF-2(512μg/ml)和PF-3(512μg/ml)未完全抑制，且仅PF-23组合达到约70％抑制率，则其被认定为二组分联用最优浓度组合。三、四组分联用中，PF-123及PF-1234(各组分浓度均为512μg/ml)，虽然抑制了90％细菌生长，但由于并无完全抑制(无高于检测线的生长)，故选择其作为最优浓度组合。
图2示出高浓度(512μg/ml)的不同组合分别对鲍曼不动杆菌金黄色葡萄球菌的抑制率。
对于耐药性鲍曼不动杆菌，四组分联用，即PF-1234达到完全抑制细菌生长。由于PF-123、PF-1234显示完全抑制，则需测试其中每种组分的最低所需浓度即最优组分浓度。
对于耐药性金黄色葡萄球菌，四组分联用的PF-1234组合抑制约90％细菌生长。由于PF123和PF-1234的抑菌效果相同，则最优浓度组合为PF-123。
图3示出：二，三和四组分联用组合对耐药的鲍曼不动杆菌的时间杀菌曲线，其中，ΜNT指MHB和菌液的混合物，PF-13(512μg/ml PF-1+512μg/ml PF-3)指二组分最优浓度联用；PF-123(512μg/ml PF-1+32μg/ml PF-2+512μg/ml PF-3)指三组分最优浓度联用；PF-1234(512μg/ml PF-1+32μg/ml PF-2+512μg/ml PF-3+32μg/ml PF-4)指四组分最优浓度联用。
三种最优浓度组合均较好的抑制作用，无明显抑菌作用。协同关系中，PF-1与PF-3起到重要作用，PF-2与PF-4的加入对协同作用影响较小。
图4示出：二,三和四组分联用组合联用组合对耐甲氧西林金黄色葡萄球 菌的时间杀菌曲线其中，ΜNT指MHB和菌液的混合物，PF-23(512μg/ml PF-2+512μg/ml PF-3)指二组分最优浓度联用；PF-123(512μg/ml PF-1+512μg/ml PF-2+512μg/ml PF-3)指三组分最优浓度联用；PF-1234(512μg/ml PF-1+512μg/ml PF-2+512μg/ml PF-3+512μg/ml PF-4)指四组分最优浓度联用。
对于耐甲氧西林金黄色葡萄球菌的结果如上图4所示，三种联用组合均有一定程度的抑菌作用。
PF-23组合相比三、四组分联用组合有着较低的抑制率，在时间杀菌曲线中很好的体现出了这一点。结合上表10的结果，PF-1、PF-2、PF-3之间互相有一定的协同作用，其中PF-1对于协同效果的贡献比其余两种组分略小，而PF-4的加入对于协同作用的影响最少。
根据上述实验结果，PF-123能够对耐甲氧西林金黄色葡萄球菌和耐药的鲍曼不动杆菌产生抑制作用。
基于上述实验结果，本发明提供一种抑制耐药细菌生长的组合物，所述组合物包含：512μg/ml苹果酸、32μg/ml富马酸和512μg/ml甘氨酸，其中，所述组合物能够抑制99％耐药鲍曼不动杆菌生长，并抑制90％耐药性金黄色葡萄球菌生长。
本发明提供的上述抑制耐药细菌生长的组合物能够用于抑制甲氧西林耐药性菌株生长并在抑制甲氧西林耐药性菌株生长的药物或日用品中具有用途。本发明提供的上述抑制耐药细菌生长的组合物能够用于抑制碳青霉烯类抗生素耐药性菌株生长并在抑制碳青霉烯类抗生素耐药性菌株生长的药物或日用品中具有用途。
根据上述实验结果，本发明提供一种药物组合物。药物组合物包含512μg/ml苹果酸、32μg/ml富马酸、512μg/ml甘氨酸以及任选存在的药学上可接受的辅料。
根据一种优选实施方式，所述药物组合物的剂型包括：口服制剂、注射制剂、经皮给药制剂、粘膜给药制剂、肺部吸入给药制剂或肠道给药制剂。
根据一种优选实施方式，所述药物组合物的剂型包括：滴剂、口服液、片剂、胶囊剂、颗粒剂、冲剂、膜剂、凝胶剂、散剂、乳剂、滴丸剂、栓剂、气雾剂、喷雾剂、粉雾剂、贴剂、贴膏剂、溶液剂、软膏剂或乳膏剂。
根据上述实验结果，本发明提供一种能够对具有碳青霉烯类抗生素耐药性的鲍曼不动杆菌和具有甲氧西林耐药性的金黄色葡萄球菌产生抑制作用的组合物，所述组合物包含512μg/ml苹果酸、32μg/ml富马酸和512μg/ml甘氨酸。
根据上述实验结果，本发明提供一种能够对具有碳青霉烯类抗生素耐药性的鲍曼不动杆菌和具有甲氧西林耐药性的金黄色葡萄球菌产生抑制作用的组合物，所述组合物包含512μg/ml苹果酸、512μg/ml富马酸、512μg/ml甘氨酸和512μg/ml马尿酸。
鲍曼不动杆菌会引起菌血症，肺炎，脑膜炎，腹膜炎，心内膜炎，以及泌尿道和皮肤感染。鲍曼不动杆菌已经成为医院感染的主要来源，尤其是重症监护室。该病菌因为抗生素的滥用，导致鲍曼不动杆菌产生抗药性，变成“多重抗药性鲍曼不动杆菌”。对抗多重抗药性鲍曼不动杆菌的方法只有用后线抗生素像老虎霉素。本发明中的组合物能够用于抑制耐药的鲍曼不动杆菌，尤其是针对可能感染鲍曼不动杆菌的患者。
耐甲氧西林金黄色葡萄球菌可引起人体多重感染，包括呼吸道感染、外科手术后感染、耳鼻喉科感染、烧伤或创伤后感染等。这种耐甲氧西林金黄色葡萄球菌对临床上多种常见的抗生素均耐药，包括青霉素类、大环内酯类、四环素类、头孢菌素类等。本发明中的组合物能够用于抑制耐甲氧西林金黄色葡萄球菌，尤其是针对可能感染金黄色葡萄球菌的患者。
本申请中的组合物PF-123或PF-1234能够以药物形式适用于患者体内、体表或其所处环境中。
Figure PCTCN2022124947-appb-000014
表11
实施例9
本申请涉及一种用于细菌性肺部感染的组合物。
向由大肠杆菌引起的小鼠肺部感染模型施用低、中、高三种剂量的代谢物组合和环丙沙星。如图5所示，代谢物组合和环丙沙星对肺部载菌量具有影响。将施用低、中、高剂量的代谢组合物和环丙沙星的小鼠的肺部组织进 行HE染色图，结果如图6所示。在对小鼠进行药物施加后，不同剂量的代谢组合物和环丙沙星均对小鼠的肺部组织中的大肠杆菌产生抑制作用。该结果也证明了由苹果酸、富马酸、甘氨酸和马尿酸构成的代谢组合物对由细菌引发的肺部感染疾病具有良好的疗效。
低、中、高剂量的代谢组合物分别为：0.5g·kg -1d -1、1.0g·kg -1d -1和1.5g·kg -1d -1。
需要注意的是，上述具体实施例是示例性的，本领域技术人员可以在本发明公开内容的启发下想出各种解决方案，而这些解决方案也都属于本发明的公开范围并落入本发明的保护范围之内。本领域技术人员应该明白，本发明说明书及其附图均为说明性而并非构成对权利要求的限制。本发明的保护范围由权利要求及其等同物限定。本发明说明书包含多项发明构思，诸如“优选地”、“根据一个优选实施方式”或“可选地”均表示相应段落公开了一个独立的构思，申请人保留根据每项发明构思提出分案申请的权利。在全文中，“优选地”所引导的特征仅为一种可选方式，不应理解为必须设置，故此申请人保留随时放弃或删除相关优选特征之权利。

Claims (15)

  1. 一种喷涂于人体表面或喷洒于人体所处环境的组合物，其包含以下物质：质量百分比为1.2％苹果酸、0.3％马尿酸、0.2％柠檬酸、0.1％甘氨酸和余量的水，所述组合物以通过抑制大肠杆菌、金黄色葡萄球菌繁殖的方式清洁人体或人体所处的环境，其中，
    所述组合物抑制大肠杆菌、金黄色葡萄球菌所使用的最低抑菌浓度比1.2％苹果酸、0.3％马尿酸、0.2％柠檬酸、0.1％甘氨酸单独抑制大肠杆菌、金黄色葡萄球菌所使用的最低抑菌浓度低2.5倍。
  2. 根据权利要求1所述的组合物在洗涤剂、抗菌药物或食品中的应用。
  3. 一种杀菌剂，包含组合式液体或气体颗粒，所述组合式液体或气体颗粒包含由高效抑菌的有机酸构成的颗粒核心和覆盖颗粒核心的由硅烷偶联剂中和的纳米级无机微孔形态的氧化锆-氧化锡复合体构成的用于保护和增加附着能力的外披膜，使得包裹有机酸的硅烷偶联剂中和的纳米级无机微孔形态的氧化锆-氧化锡复合体能够以气雾、气溶胶或小颗粒液体的方式分散于衣物、生活环境中，其中，所述有机酸被配置为：
    质量百分比为1.2％苹果酸、0.3％马尿酸、0.2％柠檬酸、0.1％甘氨酸和余量的水，所述有机酸抑制大肠杆菌、金黄色葡萄球菌所使用的最低抑菌浓度比1.2％苹果酸、0.3％马尿酸、0.2％柠檬酸或0.1％甘氨酸单独抑制大肠杆菌、金黄色葡萄球菌所使用的最低抑菌浓度低2.5倍，所述组合式液体或气体颗粒的制备方法如下：
    称量：按照1：40比例称量以重量换算的硅烷偶联剂偶联和氧化锆氧化锡复合体，称量以体积换算的有机酸；
    混合：将氧化锆氧化锡复合体分批次放入有机酸中，混匀，而后伴随搅拌动作缓慢倒入硅烷偶联剂偶联，搅拌至三相均匀，即获得浓缩后的组合式液体或气体颗粒。
  4. 一种组合物，其包含：质量百分比0.1％富马酸、1.2％苹果酸、0.3％马尿酸、0.1％甘氨酸和余量的水，其中，
    所述组合物抑制大肠杆菌、金黄色葡萄球菌所使用的最低抑菌浓度比0.1％富马酸、1.2％苹果酸、0.3％马尿酸和0.1％甘氨酸单独抑制大肠杆菌、 金黄色葡萄球菌所使用的最低抑菌浓度低2.5倍。
  5. 根据权利要求4所述的组合物在洗涤剂、抗菌药物或食品中的应用。
  6. 如权利要求4所述的组合物于抑制大肠杆菌、金属葡萄球菌、绿脓杆菌和粘质沙雷氏菌生长中的用途，其中，所述组合物能够对大肠杆菌、金属葡萄球菌、绿脓杆菌和粘质沙雷氏菌达到0.1C的抑菌效果。
  7. 一种杀菌剂，包含具有抑菌效果的第一组合物和以形成凝胶网络包裹所述第一组合物施用目标的第二组合物，所述第一组合物被配置为：质量百分比0.1％富马酸、1.2％苹果酸、0.3％马尿酸、0.1％甘氨酸和余量的水，作用于细菌胞内环境的富马酸、苹果酸、马尿酸、甘氨酸的分子直径能够小于大肠杆菌和金黄色葡萄球菌的胞膜通道直径，以使得所述第一组合物基于菌胞内部的碱性环境的改变而抑制大肠杆菌、金黄色葡萄球菌的活性，所述第一组合物抑制大肠杆菌、金黄色葡萄球菌所使用的最低抑菌浓度比单独添加0.1％富马酸、1.2％苹果酸、0.3％马尿酸或0.1％甘氨酸的杀菌剂抑制大肠杆菌、金黄色葡萄球菌所使用的最低抑菌浓度低2.5倍；
    所述第二组合物被配置为：包含多糖和蛋白质的水胶体，其中，
    所述第二组合物能够包裹所述第一组合物施用的目标，混合于所述第二组合物中的所述第一组合物能够基于对所述第一组合物施用的目标形成的压力进入所述目标内部，并在目标内部释放H +，破坏菌体内部碱性环境而抑制菌体活性。
  8. 一种抑制耐药细菌生长的组合物，所述组合物包含：512μg/ml苹果酸、32μg/ml富马酸和512μg/ml甘氨酸，其中，所述组合物能够抑制99％耐药鲍曼不动杆菌生长，并抑制90％耐药性金黄色葡萄球菌生长。
  9. 如权利要求8所述的组合物在抑制甲氧西林耐药性菌株生长中的用途。
  10. 如权利要求8所述的组合物在抑制碳青霉烯类抗生素耐药性菌株生长中的用途。
  11. 一种药物组合物，其特征在于，包含权利要求8所述的组合物以及任选存在的药学上可接受的辅料。
  12. 一种能够对具有碳青霉烯类抗生素耐药性的鲍曼不动杆菌和具有甲氧西林耐药性的金黄色葡萄球菌产生抑制作用的组合物，其特征在于，所述 组合物包含512μg/ml苹果酸、32μg/ml富马酸和512μg/ml甘氨酸。
  13. 一种能够对具有碳青霉烯类抗生素耐药性的鲍曼不动杆菌和具有甲氧西林耐药性的金黄色葡萄球菌产生抑制作用的组合物，其特征在于，所述组合物包含512μg/ml苹果酸、512μg/ml富马酸、512μg/ml甘氨酸和512μg/ml马尿酸。
  14. 一种用于细菌性肺部感染的药物组合物，其特征在于，所述药物组合物包含：苹果酸、马尿酸、富马酸、甘氨酸。
  15. 根据权利要求14所述的组合物，其特征在于，所述苹果酸、马尿酸、富马酸、甘氨酸的剂量为0.5g·kg -1d -1～1.5g·kg -1d -1。
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