CN114588144A - Bacteriostatic application of chlorogenic acid - Google Patents
Bacteriostatic application of chlorogenic acid Download PDFInfo
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- CN114588144A CN114588144A CN202210226168.9A CN202210226168A CN114588144A CN 114588144 A CN114588144 A CN 114588144A CN 202210226168 A CN202210226168 A CN 202210226168A CN 114588144 A CN114588144 A CN 114588144A
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- Prior art keywords
- chlorogenic acid
- yersinia enterocolitica
- disease
- yersinia
- concentration
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Images
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- 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
- A01N37/38—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 having at least one oxygen or sulfur atom attached to an aromatic ring system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/12—Antidiarrhoeals
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
The invention discloses an antibacterial application of chlorogenic acid, and belongs to the technical field of pharmaceutical chemistry. The invention proves that the chlorogenic acid has the effect of inhibiting yersinia enterocolitica for the first time. On the basis, the chlorogenic acid can be applied to research, development and preparation of medicines for treating enterocolitis yersinia disease caused by enterocolitis yersinia and subsequent diseases thereof, and has high medical value and wide application prospect.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to an antibacterial application of chlorogenic acid.
Background
Yersiniosis (Yersiniosis) is a common bacterial food-borne zoonosis mainly caused by yersinia enterocolitica, and the induced gastrointestinal diseases are often manifested by diarrhea, abdominal pain, nausea, vomiting, even fever and hematochezia, and sometimes can cause mesenteric lymphadenitis, reactive arthritis, erythema nodosum, respiratory and cardiovascular system damage, acute appendicitis, septicemia and the like. Yersinia enterocolitica (y. enterocolitica), a gram-negative bacillus sphaericus belonging to the family enterobacteriaceae, facultative anaerobic, is a common food-borne pathogenic bacterium that is widespread in the environment, animals and food, and can be transmitted to humans through these pathways, and can proliferate at 4 ℃, seriously threatening the health and life safety of people all over the world.
Yersinia enterocolitica is sensitive to antibiotics such as gentamicin, chloramphenicol, tetracycline, ciprofloxacin, penicillin, etc., and thus they are commonly used to treat Yersinia disease and its complications (Microb Drug resistance, 26(1): 46-53; Diagn Microbiol infection Dis,98(4): 115-. However, the abuse of antibiotics not only reduces the immunity of human bodies and breaks the flora balance in the organisms, but also stimulates the rapid emergence of drug resistance genes of bacteria, so that the bacteria generate drug resistance.
Compared with the traditional antibiotics, the natural antibacterial active substance derived from plants has the greatest characteristic of high safety, and according to literature reports, the natural antibacterial substance extracted from plants can effectively regulate the formation of bacterial biofilms and inhibit a quorum sensing system of bacteria, which shows that the generation of bacterial drug resistance is not easy to cause when the natural antibacterial active substance derived from plants is used for treating infectious diseases (Chin Med,14: 11). In addition, the natural antibacterial active substance also has the characteristics of strong antibacterial property, wide antibacterial spectrum, safe development, wide sources, economy and the like. Therefore, it is an urgent subject to develop new, naturally effective antibacterial compounds from plants, which can be used as a substitute for antibiotics to solve the problems of pathogenic infectious diseases and antibiotic resistance.
Chlorogenic Acid (CA) is a phenolic acid belonging to hydroxycinnamic acid family generated by esterification reaction of caffeic acid and quinic acid, and is mainly present in plants such as Eucommiae cortex, Lonicera Japonica flos, and Prunus humilis Bunge, and in addition, coffee bean, potato tuber, eggplantThe fruits and vegetables such as the seeds, the apples, the peaches and the like also contain chlorogenic acid. Chlorogenic acid has chemical formula of C16H18O9354.31, with a molecular weight of 4% in water at 25 ℃ and a higher solubility in hot water, is easily soluble in polar solvents such as ethanol and acetone, slightly soluble in ethyl acetate, and hardly soluble in lipophilic organic solvents such as chloroform and diethyl ether, and has the following structural formula:
chlorogenic acid, an important phenolic acid from a wide range of sources, is found to have a variety of important pharmacological actions such as oxidation resistance, inflammation resistance, virus resistance, bacteriostasis, blood sugar reduction, blood fat reduction, cancer resistance, cardiovascular disease resistance and the like. Regarding the bacteriostatic action, the prior literature mainly reports that the compound has certain inhibitory action on bacteria such as staphylococcus aureus, pseudomonas aeruginosa, bacillus subtilis, escherichia coli, streptococcus pneumoniae, shigella dysenteriae, salmonella typhimurium, klebsiella pneumoniae and salmonella enteritidis (European Food Research and Technology,238(4): 589-.
Disclosure of Invention
The invention takes yersinia enterocolitica (Y.enterocolitica) as a research object for the first time, and proves the inhibiting effect of chlorogenic acid on yersinia enterocolitica, and on the basis, the invention provides an application of natural compound chlorogenic acid, which is used for preparing a medicament for preventing and/or treating yersinia enterocolitica. Among them, yersinia enterocolitica is a disease caused by yersinia enterocolitica and includes, but is not limited to, diarrhea, abdominal pain, nausea, vomiting, and even diseases accompanied by fever and hematochezia, and the disease may cause secondary diseases such as mesenteric lymphadenitis, reactive arthritis, erythema nodosum, impaired respiratory and cardiovascular systems, acute appendicitis, and sepsis.
In the above application, the medicament for preventing and/or treating yersinia enterocolitica contains chlorogenic acid. Such drugs include, but are not limited to, the following types: chlorogenic acid is used as the only drug effect component; or chlorogenic acid as main effective component. The medicine may also contain one or more of pharmaceutically acceptable carrier, adjuvant and excipient. The dosage form of the medicament comprises but is not limited to capsules, granules, tablets, pills, sprays, suppositories, aerosols, powder aerosols, patches, oral liquid or injection.
The invention also provides a method for killing yersinia enterocolitica in vitro, which is used for killing yersinia enterocolitica for non-diagnosis and treatment purposes, and comprises the following specific steps: the chlorogenic acid aqueous solution is sprayed in the environment containing yersinia enterocolitica to achieve the purpose of killing. In the method, the concentration of the chlorogenic acid aqueous solution is 20-80 mg/mL; the concentration of the chlorogenic acid aqueous solution is preferably 40-80 mg/mL; the concentration of the chlorogenic acid aqueous solution is preferably 60-80 mg/mL; the concentration of the chlorogenic acid aqueous solution is preferably 80 mg/mL.
The invention has the beneficial effects that:
the invention proves that the chlorogenic acid has the effect of inhibiting yersinia enterocolitica for the first time. On the basis, the chlorogenic acid can be applied to research, development and preparation of medicines for treating enterocolitis yersinia disease caused by enterocolitis yersinia and subsequent diseases thereof, and has high medical value and wide application prospect.
Drawings
FIG. 1 shows the inhibition zones of Yersinia enterocolitica with different concentrations of chlorogenic acid, wherein the numbers in FIG. 1 are as follows: "1" represents water, "2" represents 40 μ g/mL gentamicin, "3" represents 80mg/mL chlorogenic acid, "4" represents 60mg/mL chlorogenic acid, "5" represents 40mg/mL chlorogenic acid, and "6" represents 20mg/mL chlorogenic acid;
FIG. 2 is a graph of the growth of Yersinia enterocolitica at different concentrations of chlorogenic acid;
FIG. 3 is a graph showing the pH-independent inhibition of Yersinia enterocolitica by chlorogenic acid, wherein the numbers in FIG. 3 are as follows: "1" means water, "2" means gentamicin 40. mu.g/mL, "3" means chlorogenic acid 80mg/mL, "4" means PBS buffer at pH 2.5.
Detailed Description
The test materials of the present invention were as follows:
yersinia enterocolitica ATCC 23715(ATCC 23715) is supplied from the Guangdong province culture Collection and stored in PRO-LAB MICROBANK culture Collection Box (PL-170) in an environment of-80 ℃.
LB broth: weighing 25g of sample, dissolving in 1L of distilled water, subpackaging the culture medium into a plurality of 250mL conical flasks, and autoclaving at 121 ℃ for 15min for later use.
LB nutrient agar: weighing 40g of sample, dissolving in 1L of distilled water, subpackaging the culture medium into a plurality of 250mL conical flasks, subpackaging each conical flask with 100mL, and autoclaving at 121 ℃ for 15min for later use.
Chlorogenic acid was obtained from Sigma, LB broth, LB nutrient agar from Qingdao Haibo Biotech, Inc., Gentamicin sulfate was obtained from Shanghai Aladdin Biotech, Inc., 8mm single-hole agar punch was obtained from Beijing Pogbos Biotech, Inc., NaOH, Na2HPO4·12H2O、NaH2PO4·2H2O was purchased from shanghai mclin biochemistry science co.
Mother liquor preparation: (1)0.2M Na2HPO4Solution: weighing 1.432g Na2HPO4·12H2O, dissolved in 20mL of distilled water. (2)0.2M NaH2PO4Solution: weighing 1.56g NaH2PO4·2H2O, dissolved in 50mL of distilled water.
0.01M PBS buffer: take 9.5mL of 0.2M Na2HPO4Solution and 40.5mL of 0.2M NaH2PO4Mixing the solutions, diluting with distilled water to 1L, adjusting pH to 7.2-7.4 with 1mol/L NaOH solution, and autoclaving at 121 deg.C for 15 min.
Terms used in the present invention have generally meanings as commonly understood by one of ordinary skill in the art, unless otherwise specified. The present invention will be described in further detail with reference to the following data in conjunction with specific examples. The following examples are intended to illustrate the invention and are not intended to limit the scope of the invention in any way.
(I) Strain activation and colony enumeration
Yersinia enterocolitica ATCC 23715 stored in the strain collection cassette was inoculated into LB nutrient broth and activated for 24 hours at 37 ℃ in a constant temperature water bath shaker at 150 rpm. Taking a certain amount of activated yersinia enterocolitica, placing into a sterile centrifuge tube, balancing, centrifuging at 4 deg.C and 6000rpm for 10min, and discarding the supernatant. And then washing the mixture for three times by using sterile 0.01M PBS buffer solution, removing the supernatant, finally adding a proper amount of PBS for heavy suspension bacterial precipitation, and performing vortex oscillation to prepare uniform PBS bacterial suspension. Absorbing a proper amount of PBS bacterial liquid in an ultraclean workbench, adjusting to zero by using the PBS liquid, measuring the light absorption value of the PBS bacterial liquid under 600nm by using an Evolution 201 ultraviolet-visible spectrophotometer, then, carrying out gradient dilution on the bacterial liquid by using the PBS liquid, selecting a proper dilution multiple, absorbing 2 mu L of the PBS bacterial liquid by using a pipette gun, placing the PBS bacterial liquid in the center of a blood counting plate, observing under an optical microscope, carrying out colony counting, and calculating to obtain the concentration of the bacterial liquid, thereby determining the corresponding relation between the OD value of the PBS bacterial suspension and the concentration (CFU/mL) of the bacterial liquid. Adjusting the concentration of PBS bacterial suspension to 1X 108CFU/mL, spare.
(II) determination of bacteriostatic Activity
The bacteriostatic activity of chlorogenic acid against yersinia enterocolitica was tested from the following angles: 1. pour plate method; 2. growth curve method; 3. verification of pH-independent antibacterial effect of chlorogenic acid.
1. Pour plate method
The zone of inhibition of Yersinia enterocolitica by chlorogenic acid was determined by pour plate assay (ACS Appl Mater Interfaces,10(17): 15163-15173). Firstly, chlorogenic acid aqueous solution with the concentration of 20mg/mL, 40mg/mL, 60mg/mL and gentamicin aqueous solution with the concentration of 40 μ g/mL are respectively prepared, and vortex oscillation is carried out to fully mix the components. Heating and melting the prepared sterile LB solid culture medium by a microwave oven, standing at normal temperature, and cooling until the bottom of the conical flask can be held by hands without scalding hands (the temperature is about 50 ℃). Taking 1mL PBS bacterial suspension to carry out gradient dilution until the concentration is 2 multiplied by 106CFU/mL, suctionAdding 700 μ L of the bacterial liquid into 100mL of cooled LB solid culture medium to make the final concentration of the bacterial liquid about 104CFU/mL, mixing well, pouring the culture medium into a sterile culture dish quickly, and standing until the culture medium is completely solidified. Finally, punching a hole by using a sterilized 8mm single-hole agar puncher, removing the agar punched with the hole by using a sterilized toothpick, respectively sucking 200 mu L of sterile water, 40 mu g/mL of gentamicin and chlorogenic acid solutions with different concentrations by using a pipette, sequentially adding the sterile water, the gentamicin solutions and the chlorogenic acid solutions into corresponding holes, standing the mixture in a refrigerator at 4 ℃ for 4 hours to ensure that the medicaments are fully absorbed by the agar, and then, vertically placing the plate in a constant-temperature incubator at 37 ℃ for culturing for 12 hours. The diameter of the bacteriostatic circle is measured and the photographing record is carried out by the bacteriostatic circle measuring function of the full-automatic colony counter, and three groups of parallel experiments are set for each concentration.
The inhibition zone of different concentrations of chlorogenic acid on yersinia enterocolitica is shown in figure 1, and the diameter of the inhibition zone is shown in table 1. As can be seen from FIG. 1, chlorogenic acid has a significant growth inhibitory effect on Yersinia enterocolitica. When the chlorogenic acid concentration is between 40mg/mL and 80mg/mL, the diameter of the inhibition zone is increased in a concentration-dependent manner (the diameter of the inhibition zone is increased from 11.8mm to 14.3mm), which indicates that the bacteriostatic activity of the chlorogenic acid is in a concentration-dependent manner. When the concentration of chlorogenic acid is 20mg/mL, no obvious inhibition zone is observed compared with the gentamicin positive control group.
TABLE 1
Note: "-" indicates no zone of inhibition.
2. Growth curve method
The inhibitory effect of chlorogenic acid on Yersinia enterocolitica was determined by growth curve method (J Agric Food Chem,66(45): 12088-12101). The growth curve of yersinia enterocolitica was determined by a microorganism growth curve analyzer. Opening an aseptic 48-pore plate matched with a microorganism growth curve tester in an ultra-clean workbench, and respectively adding 100 mu L of water, 400 mu g/mL of gentamicin, 20mg/mL of chlorogenic acid, 40mg/mL of chlorogenic acid, 60mg/mL of chlorogenic acid and 80mg/mL of chlorogenic acid into the 48-pore plateAdding 900 μ L LB liquid culture medium into each well, mixing to obtain final concentrations of gentamicin 40 μ g/mL and chlorogenic acid 2, 4, 6, and 8mg/mL, and adding 10 μ L of 1 × 108Mixing CFU/mL PBS bacterial liquid uniformly to make the initial concentration of bacterial liquid in each hole be 1 × 106CFU/mL, each concentration set up three groups of parallel experiments. Setting instrument parameters: the OD value was measured at 37 ℃ and 800rpm every 2 hours, and the temperature of the circulating water cooling system was set to 30 ℃. And stopping the experiment when the growth of the bacteria in the negative control group reaches the plateau stage, and drawing a growth curve by using the OD value measured at each time point.
The growth curves of different concentrations of chlorogenic acid against yersinia enterocolitica are shown in figure 2. All chlorogenic acid-treated groups OD compared to water-treated negative control group600There is a significant reduction. When the concentration of the chlorogenic acid is 2, 4 and 6mg/mL, the growth of the yersinia enterocolitica is obviously inhibited at the beginning, and the trend lasts for 4-8h, which indicates that the chlorogenic acid has partial inhibition effect on the yersinia enterocolitica. However, at chlorogenic acid concentrations of 8 and 10mg/mL, the growth curve appeared as a horizontal line, OD throughout the experiment600Always at the initial value and remained unchanged, this trend was the same as for the growth curve of the gentamicin group, indicating that chlorogenic acid completely inhibited yersinia enterocolitica. Furthermore, from the general trend of the growth curve it can be concluded that chlorogenic acid has a concentration-and time-dependence on the bacteriostatic effect of yersinia enterocolitica.
3. Verification of pH-independent antibacterial action of chlorogenic acid
According to the prior reports (Biological and Pharmaceutical Bulletin,41(2): 208-. In order to eliminate the influence of the acidic property of the chlorogenic acid on the bacteriostatic action of the yersinia enterocolitica, a design experiment proves that the bacteriostatic action of the chlorogenic acid on the yersinia enterocolitica is pH-independent.
The pH of the 80mg/mL chlorogenic acid solution was 2.5 by using a pH meter, and the pH of the PBS buffer was adjusted to 2.5 by using a 1mol/L NaOH solution. The zone of inhibition of yersinia enterocolitica by sterile water, gentamicin 40. mu.g/mL, chlorogenic acid 80mg/mL, pH 2.5 PBS buffer was also determined by pour-plate method, and three sets of parallel experiments were performed for each concentration.
The inhibition zone of chlorogenic acid and PBS buffer solution on yersinia enterocolitica is shown in FIG. 3, and the diameter of the inhibition zone is shown in Table 2. As can be seen from fig. 3, 80mg/mL of chlorogenic acid has significant bacteriostatic activity (zone diameter of 13.5mm), while no significant zone was observed in PBS buffer having the same pH value as 80mg/mL of chlorogenic acid solution (pH 2.5), indicating that the PBS buffer has no bacteriostatic effect. The experiment proves that the acidic environment can not inhibit yersinia enterocolitica, thereby eliminating the pH-dependent bacteriostatic action of chlorogenic acid.
TABLE 2
Note: "-" indicates no zone of inhibition.
In conclusion, the pour plate method and the growth curve method prove that the chlorogenic acid has a remarkable bacteriostatic action on yersinia enterocolitica, and the bacteriostatic action has concentration dependence and time dependence. Meanwhile, a pH-independent bacteriostasis test proves that the bacteriostasis of the chlorogenic acid is independent of the acidity characteristic and pH independent.
The foregoing is directed to preferred embodiments of the present invention, other and further embodiments of the invention may be devised without departing from the basic scope thereof, and the scope thereof is determined by the claims that follow. However, any simple modification, equivalent change and modification of the above embodiments according to the technical essence of the present invention are within the protection scope of the technical solution of the present invention.
Claims (10)
1. Application of chlorogenic acid in preparing medicine for preventing and/or treating enterocolitis yersinia disease and its secondary disease is provided.
2. The use according to claim 1, wherein the yersinia enterocolitica is a disease caused by yersinia enterocolitica with symptoms including diarrhea, abdominal pain, nausea and vomiting, even with fever and bloody stool.
3. The use of claim 1, wherein the secondary disease is other disease caused by yersinia enterocolitica disease, including one or more of mesenteric lymphadenitis, reactive arthritis, erythema nodosum, impaired respiratory and cardiovascular systems, acute appendicitis and sepsis.
4. The use according to claim 1, wherein the medicament contains chlorogenic acid.
5. The use of claim 4, wherein the medicament is chlorogenic acid as the sole active ingredient or chlorogenic acid as the main active ingredient.
6. The use of claim 4, wherein the medicament further comprises one or more of pharmaceutically acceptable carriers, excipients and excipients.
7. The use according to claim 4, wherein the pharmaceutical dosage form comprises, but is not limited to, capsules, granules, tablets, pills, sprays, suppositories, aerosols, dusts, patches, oral liquids or injections.
8. A method for killing yersinia enterocolitica with a non-diagnosis purpose is characterized by comprising the following steps: the chlorogenic acid aqueous solution is sprayed in the environment containing yersinia enterocolitica to achieve the purpose of killing.
9. The method according to claim 8, wherein the concentration of the aqueous chlorogenic acid solution is 40-80 mg/mL.
10. The method according to claim 9, wherein the concentration of the aqueous chlorogenic acid solution is 60-80 mg/mL.
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