CN116747221A - Antibacterial composition and preparation method and application thereof - Google Patents
Antibacterial composition and preparation method and application thereof Download PDFInfo
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- CN116747221A CN116747221A CN202310979741.8A CN202310979741A CN116747221A CN 116747221 A CN116747221 A CN 116747221A CN 202310979741 A CN202310979741 A CN 202310979741A CN 116747221 A CN116747221 A CN 116747221A
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- shikimic acid
- antibacterial
- antibiotics
- staphylococcus aureus
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- 230000000844 anti-bacterial effect Effects 0.000 title claims abstract description 38
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- JXOHGGNKMLTUBP-HSUXUTPPSA-N shikimic acid Chemical compound O[C@@H]1CC(C(O)=O)=C[C@@H](O)[C@H]1O JXOHGGNKMLTUBP-HSUXUTPPSA-N 0.000 claims abstract description 79
- JXOHGGNKMLTUBP-JKUQZMGJSA-N shikimic acid Natural products O[C@@H]1CC(C(O)=O)=C[C@H](O)[C@@H]1O JXOHGGNKMLTUBP-JKUQZMGJSA-N 0.000 claims abstract description 79
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Classifications
-
- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/429—Thiazoles condensed with heterocyclic ring systems
- A61K31/43—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
- A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine
- A61K31/546—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine containing further heterocyclic rings, e.g. cephalothin
-
- 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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- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to the technical field of antibiosis, and particularly relates to an antibiosis composition, a preparation method and application thereof. The antibacterial composition provided by the invention comprises the following components in parts by weight: 8-32 parts of antibiotics and 312-625 parts of shikimic acid. The antibacterial composition provided by the invention has the advantages that the natural traditional Chinese medicine extract shikimic acid is combined with antibiotics to inhibit or kill drug-resistant bacteria, the dosage of the antibiotics can be obviously reduced, adverse reactions and side effects are reduced, the safety of medication is improved, and the shikimic acid and the antibiotics can generate obvious synergistic effect and have obvious inhibition effect on drug-resistant bacteria such as staphylococcus aureus or escherichia coli. The embodiment shows that the shikimic acid which is a traditional Chinese medicine extract with stronger in-vitro antibacterial effect on methicillin-resistant staphylococcus aureus is screened, and when shikimic acid and ceftiofur sodium are used in combination, the methicillin-resistant staphylococcus aureus can be killed within 2 hours at maximum, and the effect is obviously better than that of the shikimic acid and the ceftiofur sodium which are used independently.
Description
Technical Field
The invention belongs to the technical field of antibiosis, and particularly relates to an antibiosis composition, a preparation method and application thereof.
Background
Staphylococcus aureus (Staphylococcus aureus) is a bacterium causing endocarditis, bacteremia, pneumonia, skin and soft tissue infection and other series of diseases, and is mainly treated and killed by antibiotics such as penicillin, cephalosporin, erythromycin, lincomycin, clindamycin and the like at present. However, with the overuse of antibiotics, bacteria have developed various different drug resistance mechanisms under tremendous selection pressure, which ultimately lead to the emergence of superbacteria.
Methicillin-resistant staphylococcus aureus (MRSA) is a common multidrug-resistant and highly virulent pathogen in staphylococcus aureus. Since the first discovery in the uk in 1961, MRSA has spread around the world and has become one of the most important pathogens leading to community availability and healthcare related infections. The spread of drug-resistant bacteria not only leads the death rate of people to rise sharply, but also threatens economic animals such as cattle, sheep, pigs and chickens, and brings great economic loss for agricultural production. In the latter antibiotic era, the development speed of antibacterial drugs is far lower than the generation and transmission speed of bacterial drug resistance. For this purpose, combination drugs have been proposed to combat resistant bacteria.
The traditional Chinese medicine is used as a natural medicine, a large number of potential antibacterial adjuvants exist in the traditional Chinese medicine, and the compounds have wide distribution, novel structure and good biological safety, but have weak direct sterilization activity and rarely generate survival pressure on bacteria, so that the frequency of drug resistance genes in bacterial populations can be controlled to a certain extent. The traditional Chinese medicine extract and the antibiotics can be used together to effectively resist drug-resistant bacteria, but the antibiotics are mainly used for killing, so that adverse reactions and side effects can be caused, and the safety is low.
Thus, there is a need for an antimicrobial composition that reduces the amount of antibiotics or reduces adverse effects and side effects associated with antibiotics.
Disclosure of Invention
Therefore, the invention aims to provide the antibacterial composition, wherein the shikimic acid which is a medicinal and edible traditional Chinese medicine extract is combined with antibiotics to inhibit or kill drug-resistant bacteria, so that the dosage of the antibiotics can be obviously reduced, adverse reactions and side effects are reduced, the safety of medication is improved, and the shikimic acid and the antibiotics can generate obvious synergistic effect and have obvious inhibition effect on drug-resistant bacteria such as staphylococcus aureus or escherichia coli.
In order to achieve the above object, the present invention provides the following technical solutions:
the invention provides an antibacterial composition which comprises the following components in parts by weight: 8-32 parts of antibiotics and 312-625 parts of shikimic acid.
Preferably, the antibiotic comprises a beta-lactam antibiotic.
Preferably, the β -lactam antibiotic comprises penicillin, ampicillin, amoxicillin or ceftiofur.
Preferably, the ceftiofur comprises ceftiofur sodium.
The invention provides a preparation method of the antibacterial composition, which comprises the following steps: mixing the antibiotic and shikimic acid to obtain the antibacterial composition.
The invention also provides application of the antibacterial composition in preparation of antibacterial drugs.
Preferably, the bacteria include drug resistant bacteria.
Preferably, the drug-resistant bacteria include staphylococcus aureus and/or escherichia coli.
Preferably, the staphylococcus aureus comprises methicillin-resistant staphylococcus aureus.
The invention also provides an antibacterial drug, and the effective components of the antibacterial drug comprise the antibacterial composition according to the technical scheme.
The beneficial effects are that:
the invention provides an antibacterial composition, which comprises antibiotics and shikimic acid, wherein the shikimic acid is taken as a natural traditional Chinese medicine extract, and can generate remarkable synergistic effect when being combined with the antibiotics, so that the dosage of the antibiotics is reduced, adverse reactions and side effects are reduced, the safety of medication is improved, and remarkable inhibition effect on drug-resistant bacteria such as staphylococcus aureus or escherichia coli can be generated. According to the description of the embodiment, the invention starts from the medicinal and edible traditional Chinese medicine extract, and through the test of a prepared growth curve and broth micro dilution chessboard method, the traditional Chinese medicine extract monomer shikimic acid with stronger in-vitro antibacterial effect on methicillin-resistant staphylococcus aureus is screened, when the extract and ceftiofur sodium are used for combined administration, methicillin-resistant staphylococcus aureus (MRSA) is killed within 2 hours at maximum, and the effect is obviously better than that of each single administration of shikimic acid and ceftiofur sodium.
The antibacterial composition provided by the invention can be used for preparing medicines with antibacterial effect, is expected to provide reference for developing new auxiliary medicines for treating severe infection diseases by ceftiofur sodium, improves the treatment benefit, and provides a new research thought and development direction for solving the increasingly serious drug resistance problem of ceftiofur sodium.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings that are required to be used in the embodiments will be briefly described below.
FIG. 1 is a graph of sterilization curves for 1/4MIC of ceftiofur sodium in example 1 in combination with SA at various concentrations;
FIG. 2 is a graph showing the sterilization profile of 1/8MIC of ceftiofur sodium in example 1 in combination with SA at various concentrations;
FIG. 3 is a graph showing the effect of SA at various concentrations on cell viability in example 2;
FIG. 4 is a graph showing the effect of different treatments on survival of mice model infected with MRSA in example 3;
FIG. 5 is a graph showing the results of liver tissue load at 24h,48h and 72h for various treated infected MRSA mouse models in example 4;
FIG. 6 is a graph showing the results of the spleen tissue load of the infected MRSA mouse model at 24h,48h and 72h after different treatments in example 4;
FIG. 7 is a graph showing the results of the different treatment of example 4 in which kidney tissue load of MRSA mice model was measured at 24h,48h and 72 h;
FIG. 8 is a graph of survival of mice after SA at body weight doses of 150, 100 and 75mg/kg, respectively, in example 5;
FIG. 9 is a graph of liver tissue sections of mice model infected with MRSA after different treatments in example 6, control group (upper left), MRSA group (upper right), CF group (lower left), CF+SA group (lower right);
FIG. 10 is a graph of spleen tissue sections of mice model infected with MRSA after various treatments in example 7, control group (upper left), MRSA group (upper right), CF group (lower left), CF+SA group (lower right);
fig. 11 is a graph of kidney tissue sections of a mouse model infected with MRSA after various treatments in example 8, a control group (upper left), an MRSA group (upper right), a CF group (lower left), and a cf+sa group (lower right).
Detailed Description
The invention provides an antibacterial composition which comprises the following components in parts by weight: 8-32 parts of antibiotics and 312-625 parts of shikimic acid.
The antibacterial composition comprises 8-32 parts by weight of antibiotics, preferably 8-16 parts by weight, and more preferably 8 parts by weight. The antibiotics of the present invention preferably include beta-lactam antibiotics; the beta-lactam antibiotic preferably comprises penicillin, ampicillin, amoxicillin or ceftiofur, more preferably ceftiofur, and even more preferably ceftiofur sodium. The source of the antibiotic is not particularly limited, and conventional commercial products can be used.
The antibacterial composition comprises 312 to 625 parts by weight, preferably 400 to 625 parts by weight, more preferably 500 to 625 parts by weight, still more preferably 625 parts by weight of shikimic acid based on the weight of the antibiotic. The shikimic acid is preferably shikimic acid extracted from fructus Anisi Stellati. The shikimic acid provided by the invention has a synergistic effect on improving the antibacterial efficacy of beta-lactam antibiotics. The source of shikimic acid of the star anise extract is not particularly limited, and the star anise extract can be prepared by adopting conventional commercial products or by self. As in the specific examples of the present invention, the shikimic acid is available from Sichuan Hengruitong Biotechnology Co., ltd, under the product number 04020149.
The antibacterial composition provided by the invention is used for combining shikimic acid with antibiotics, so that remarkable synergistic effect can be generated, the consumption of antibiotics is reduced, adverse reactions and side effects are reduced, the safety of the medicine is improved, and remarkable inhibition effect can be generated on drug-resistant bacteria such as staphylococcus aureus or escherichia coli.
The invention provides a preparation method of the antibacterial composition, which comprises the following steps: mixing the antibiotic with shikimic acid to obtain the antibacterial composition. The mixing mode is not particularly limited, and the mixing can be carried out uniformly by adopting a conventional mixing method in the field.
The invention also provides application of the antibacterial composition in preparation of antibacterial drugs. In the present invention, the bacteria preferably include drug-resistant bacteria; the drug-resistant bacteria of the present invention preferably comprise staphylococcus aureus and/or escherichia coli, more preferably staphylococcus aureus, and even more preferably methicillin-resistant staphylococcus aureus. The methicillin-resistant staphylococcus aureus is preferably methicillin-resistant staphylococcus aureus standard bacterium ATCC33591.
The invention also provides an antibacterial drug, and the effective components of the antibacterial drug comprise the antibacterial composition according to the technical scheme.
The antibacterial composition provided by the invention can be used for preparing medicines with antibacterial effect, is expected to provide reference for developing new auxiliary medicines for treating severe infection diseases by ceftiofur sodium, improves the treatment benefit, and provides a new research thought and development direction for solving the increasingly serious drug resistance problem of ceftiofur sodium.
For further explanation of the present invention, the antibacterial compositions provided by the present invention are described in detail below with reference to the accompanying drawings and examples, but they should not be construed as limiting the scope of the present invention.
Example 1
Antibacterial effect of shikimic acid SA and beta-lactam antibiotics on MRSA standard strain ATCC33591
Determination of Minimum Inhibitory Concentration (MIC) of a single drug
MIC values for each individual were determined using the American Clinical Laboratory Standards Institute (CLSI) recommended micro-broth dilution method using MRSA standard strain ATCC33591 as a subject.
Preparation of bacterial suspension: the recovered ATCC33591 was streaked on brain heart infusion agar, cultured at 37℃for 24 hours, and then the monoclonal colony was picked up in MH broth and cultured at 37℃for 8 hours with shaking. The culture broth was diluted with a blank MH to a turbidity of 0.5 McAb (broth concentration of about 10) 8 CFU/mL), and diluting the bacterial liquid 1000 times to obtain a test bacterial liquid with a final concentration of 10 5 CFU/mL。
Trace broth dilution assay: stock solutions of test drugs (shikimic acid SA, penicillin, ampicillin, amoxicillin and ceftiofur sodium) were diluted to a certain high concentration, the doubling ratios were diluted to 10 concentrations (1 st well to 10 th well) of 5mg/mL, 2.5mg/mL, 1.25mg/mL, 0.625mg/mL, 0.3125mg/mL and so on for 100. Mu.L per well, and the above bacterial suspensions were added to 1-10 wells (the order of addition was low concentration to high concentration in order of preventing contamination of high concentration drug). Two groups of controls were set up for each experiment: wells 11 were positive control, test bacterial fluid control, and wells 12 were broth blank control, negative control. After incubation at 37℃for 24h, the results were observed.
And (3) result judgment: the minimum concentration at which no bacterial growth was observed was the MIC of the drug, and at this time the positive control had bacterial growth, while the negative control was still clear to determine that the result was valid, otherwise, it was not necessary to redo. Two rows of each drug were made in parallel and repeated twice. MIC detection results of Shikimic Acid (SA), penicillin (Penicillin), ampicillin (Ampicillin), amoxicillin (Amoxicillin) and Ceftiofur sodium (Ceftiofur, CF) are shown in Table 1.
Combined drug experiments
The combined sensitization test is carried out by adopting a chessboard method, based on the MIC test results of the shikimic acid SA and each beta-lactam antibiotic single drug, the 2-fold, 1/2-fold, 1/4-fold, 1/8-fold and 1/16-fold MIC of the two drugs are designed by adopting a broth dilution chessboard method to carry out 6X 6 combination, and the shikimic acid and each antibiotic are diluted to a specific drug concentration by using MH broth and added into each well of a 96-well plate. In addition, controls were made for the MIC, negative (broth only) and positive wells (broth only and MRSA standard strain ATCC 33591) of both individual drugs simultaneously. Bacterial suspension is prepared into bacterial solution according to the preparation method of the bacterial suspension, the bacterial solution is added into each hole of a 96-well plate, and is kept stand in a constant temperature incubator at 37 ℃ for 24 hours, then the results are observed and recorded, the combined MIC of shikimic acid SA and each beta-lactam antibiotic under the combined action is obtained, and then the FICI is calculated according to the formula of FICI= (MIC for combination A/MIC for combination A) + (MIC for combination B/MIC for combination B). Staphylococcus aureus ATCC29213 was used as a quality control strain for each experiment. The results are shown in Table 1.
TABLE 1 combined anti-MRSA effect of SA and beta lactam antibiotics
Note that: FICI is less than or equal to 0.5, and is synergistic; FICI < 1 is 0.5 and is added; FICI is more than 1 and less than 2, and is irrelevant; FICI > 2, antagonism.
As can be seen from Table 1, the minimum inhibitory concentration of shikimic acid SA against MRSA standard strain ATCC33591 was determined to be 5mg/mL. In addition, SA also shows synergistic effects with other beta-lactam antibiotics.
Bacterial growth curve under combined action of SA and ceftiofur sodium
Preparation of antibacterial drugs: taking MRSA standard strain ATCC33591 as a study object, according to the test result of single drug Minimum Inhibitory Concentration (MIC), ceftiofur sodium and shikimic acid stock solution are diluted by MH broth to the following concentrations: ceftiofur sodium 1/4MIC, ceftiofur sodium 1/8MIC, shikimic acid 1/16MIC, ceftiofur sodium 1/4 MIC+shikimic acid 1/8MIC, ceftiofur sodium 1/4 MIC+shikimic acid 1/16MIC, ceftiofur sodium shikimic acid 1/8 MIC+shikimic acid 1/8MIC, ceftiofur sodium 1/8 MIC+shikimic acid 1/16MIC.
Preparation of bacterial suspension: colonies of the single MRSA standard strain ATCC33591 were picked up with a sterile stick, inoculated into a Mirabilitum tube containing sterile PBS, and adjusted to 0.5 Mirabilitum with a Mirabilimeter at a bacterial concentration of about 10 8 CFU/mL; then the bacterial liquid is treatedDiluted 1000 times and used as test bacterial liquid with the final concentration of 10 5 CFU/mL。
And (3) drawing a growth curve: three groups of the antibacterial drug combinations are arranged in parallel, and are respectively added into sterile 96-well plates, wherein the volume of each group of the 96-well plates is 100 mu L. Finally, 100 mu L of the bacterial suspension is added into each hole, a 96-well plate cover is covered, and the mixture is placed in an enzyme-labeled instrument with the constant temperature of 37 ℃ for culture. The OD value of the bacterial liquid is measured at 600nm wavelength of the enzyme label instrument every one hour (24 time points) within 0-24 hours. The OD thus obtained is then used 600 The values are plotted against time for bacterial growth. The results are shown in FIGS. 1 and 2.
As shown by the results in FIG. 1, SA with 1/8MIC alone has little bacteriostatic effect; the ceftiofur sodium with the MIC of 1/4 is combined with SA with the MIC of 1/16, the quantity of the staphylococcus aureus is greatly reduced in the first 12 hours, and the effect is continued after 18 hours; and after 1/4MIC of ceftiofur sodium and 1/8MIC of SA treatment, the staphylococcus aureus ATCC33591 can be completely killed within 2 hours.
The results in FIG. 2 show that SA with 1/8MIC alone has little bacteriostatic effect; the ceftiofur sodium with the concentration of 1/8MIC is combined with SA with the concentration of 1/16MIC, the quantity of the staphylococcus aureus is greatly reduced in the first 8 hours, and the effect is continued after 10 hours; and 1/8MIC of SA and 1/8MIC of ceftiofur sodium, the staphylococcus aureus ATCC33591 can be completely killed within 2 hours.
Example 2
Toxicity test of SA alone on Bovine Mammary Epithelial Cells (BMECs)
The purpose of the experiment is as follows: toxicity of SA to BMECs was verified to determine the in vivo safety of the drug.
The experimental method comprises the following steps:
(1) BMECs were seeded into 96-well plates at a density of 100000/mL, 100. Mu.L/well, 5% CO 2 The incubator was incubated at 37℃for 24 hours.
(2) When the cells were grown to about 80%, 96 wells were divided into 8 groups, and culture solutions (medium components: 89% 1640, 10% fetal bovine serum, 1% green chain mycin solution), 100. Mu.L/well, each of which had been added with 2.5mg/mL, 1.875mg/mL, 1.25mg/mL, 0.625mg/mL, 0.313mg/mL, 0.156mg/mL, 0.078mg/mL, and 0mg/mL SA, were added thereto, and cultured for 24 hours.
(3) 10 mu L of CCK-8 reagent is added into each hole, and the mixture is cultured for 1 to 4 hours. 450nm detection wavelength, 600nm reference wavelength.
(4) Each group had 6 duplicate wells and a blank (no cells, drug only and CCK-8) was set up
The cell viability was calculated as follows:
cell viability (%) = (OD Drug -OD Blank )/(OD Control -OD Blank )×100％。
OD Drug : drug (SA) group, OD Blank : blank control group (SA and CCK-8 added), OD Control : drug-free (SA) group; the results are shown in Table 2 and FIG. 3.
TABLE 2 results of cell viability at different concentrations of SA
As can be seen from Table 2 and FIG. 3, SA of 0.625mg/mL or less showed no significant effect on cell viability in the SA-treated groups at each concentration compared to the non-dosed control groups.
Example 3
MRSA high concentration lethal model
After one week of adaptive feeding, 50 6-8 week BALB/c female mice were randomly divided into 5 groups at 10 per group. Group 1 was a blank control group, and the other 4 groups were intraperitoneally injected with 0.5mL of MRSA bacterial suspension (final concentration 7X 10) 8 CFUs/alone). After bacterial infection for 2 hours, mice in the blank group were injected with 300. Mu.L of PBS buffer (pH 7.4), and other 4 groups of mice were respectively injected with 300. Mu.L of PBS buffer (pH 7.4) in the abdominal cavity, and were designated as MRSA groups; 300. Mu.L of SA (50 mg/kg by weight of mice) was recorded as SA group; 300. Mu.L of ceftiofur sodium (5 mg/kg injected by weight of mice) was recorded as CF group; 300. Mu.L of SA+ceftiofur sodium (50 mg/kg+5mg/kg of mice were injected by weight), designated as SA+CF group. Survival of each group of mice was calculated over 96 hours after administration of the antibacterial drug treatment. The results are shown in Table 2 and FIG. 4.
TABLE 2 survival of infected MRSA mice model after different treatments (%)
As can be seen from table 2 and fig. 4, the mortality rate of mice was extremely high in 48 hours after infection, the mortality rate of each of the MRSA group (not dosed), the SA group, and the ceftiofur sodium group reached 20% -50%, while the survival rate of the combination group was 100%, which is significantly higher than that of the other groups, indicating that the combination of SA and ceftiofur sodium can significantly improve the survival rate of mice infected with bacteremia.
Example 4
MRSA low concentration bacteremia model
After one week of adaptive feeding, 42 BALB/c female mice were randomly divided into 6 groups at a number of 7 per group. Each mouse was intraperitoneally injected with 0.5mL of MRSA bacterial suspension (final concentration 1X 10) 8 CFUs/alone) established MRSA low concentration bacteremia models. After bacterial infection for 2h, 6 groups of mice were each intraperitoneally injected with 300 μl of PBS buffer (pH 7.4), designated as MRAS group; 300. Mu.L of SA (50 mg/kg by weight of mice) was recorded as SA group; 300. Mu.L of ceftiofur sodium (5 mg/kg injected by weight of mice) was recorded as CF group; 300. Mu.L of SA+ceftiofur sodium (50 mg/kg+5mg/kg injected by weight of mice) was designated as CF+SA1 group; 300. Mu.L of SA+ceftiofur sodium (75 mg/kg+5mg/kg of mice weight injected) was designated as CF+SA2 group; 300. Mu.L of SA+ceftiofur sodium (100 mg/kg+5mg/kg injected by weight of mice) was designated as CF+SA3 group. Taking liver, spleen and kidney tissues of each group of mice at 24h,48h and 72h, and adopting a plate colony technique to count the colonies, wherein the specific steps are as follows: each group of surviving mice was sacrificed at 24h,48h,72h time points, their liver, spleen, kidney tissue organs were taken, weighed, homogenized, and then 10-fold diluted with PBS to a series of concentrations: 10 -1 ，10 -2 ，10 -3 And the like, 100 mu L of PBS (phosphate buffered saline) with proper dilution concentration is selected, uniformly coated on an MH agar plate by a sterile rod, the observation result is obtained after the culture is carried out for 24 hours at 37 ℃, a plate with 30-300 colonies growing is selected for colony counting, and the results are shown in tables 3-5 and figures 5-7.
TABLE 3 colony count results (CFU) of liver tissue at 24h,48h,72h time points
TABLE 4 colony count results (CFU) of spleen tissue at 24h,48h,72h time points
| MRSA | CF | SA | CF+SA1 | CF+SA2 | CF+SA3 | |
| 24h | 1.2×10 7 | 9.1×10 5 | 7.5×10 5 | 6.0×10 5 | 6.9×10 5 | 4.4×10 4 |
| 48h | 2.2×10 6 | 2.9×10 5 | 2.5×10 4 | 2.8×10 4 | 1.5×10 4 | 4.6×10 3 |
| 72h | 4.0×10 5 | 5.7×10 4 | 7.0×10 4 | 2.1×10 4 | 8.4×10 3 | 6.7×10 3 |
TABLE 5 colony count results (CFU) of spleen tissue at 24h,48h,72h time points
| MRSA | CF | SA | CF+SA1 | CF+SA2 | CF+SA3 | |
| 24h | 1.6×10 7 | 6.6×10 5 | 3.6×10 6 | 1.0×10 5 | 8.3×10 4 | 2.0×10 4 |
| 48h | 3.0×10 7 | 1.2×10 6 | 2.9×10 6 | 1.5×10 5 | 2.2×10 4 | 2.2×10 4 |
| 72h | 4.3×10 5 | 6.7×10 4 | 7.0×10 4 | 1.0×10 4 | 1.7×10 4 | 1.0×10 4 |
As can be seen from tables 2 to 4 and FIGS. 5 to 7, the combined group can greatly reduce the bacterial load of liver, spleen and kidney tissues compared with the MRSA group, has good treatment effect and is dose-dependent. The combination group was overall superior to the SA group and ceftiofur sodium group, suggesting that this may be the effect of both combined mechanism kills.
Example 5
Acute toxicity test
The acute toxicity test of mice is carried out by referring to the guidelines for acute toxicity study of Chinese chemical drugs (H-GPT 1-1) and European chemical ecotoxicology and toxicology centers. Each group of 6 female BALB/c mice (6-8 weeks old, 18-20g weight) were intraperitoneally injected with shikimic acid SA at doses of 150mg/kg, 100mg/kg and 75mg/kg, respectively, according to the weight of the mice. Mice were injected with PBS as a Control group (Control). Each group of mice was observed for 72h for toxic symptoms, abnormal behavior, and survival. The results are shown in FIG. 8.
As shown in FIG. 8, each group of mice has no toxic symptoms and abnormal behaviors within 72 hours, and has no death phenomenon, which indicates that 150mg/kg has no influence on the mice, and shikimic acid has better safety.
Example 6
Histopathological examination
After one week of adaptive feeding, 28 6-8 week BALB/c female mice were randomly divided into 4 groups at a number of 7 per group. One group was a blank group, and the other 3 groups were each intraperitoneally injected with 0.5mL of MRSA bacterial suspension (final concentration 1X 10) 8 CFUs/alone). After bacterial infection for 2h, 3 groups of mice were each intraperitoneally injected with 300 μl of PBS buffer (pH 7.4), designated as MRSA group; 300. Mu.L of ceftiofur sodium (5 mg/kg injected by weight of mice) was recorded as CF group; 300. Mu.L of SA+ceftiofur sodium (75 mg/kg+5mg/kg of mice were injected by weight), designated as SA+CF group. The dose and the administration mode are the same as those of the mortality test, and the administration is carried out again after 12 hours. After 24h, mice were sacrificed by cervical dislocation, the liver, spleen and kidney of the mice were aseptically removed and fixed in 4% formaldehyde. The liver, spleen and kidney tissues are subjected to procedures such as dehydration, paraffin embedding, slicing, HE staining and the like in sequence, and pictures are photographed and recorded under an optical microscope. The results are shown in FIGS. 9-11.
As can be seen from fig. 9, the infected group showed liver pathological changes such as altitude edema of hepatocytes, balloon-like changes, and a large number of small vacuoles appeared in the cytoplasm; the treatment group received some relief; FIG. 10 shows that the pathological changes of megakaryocyte and neutrophil increase in the spleen of the infected group are effectively alleviated in the treatment group; FIG. 11 shows that the pathological changes of a large amount of homogeneous red dye liquid in the lumen of kidney tissues of an infected group are effectively alleviated, and the effect of the combined treatment group is particularly obvious.
According to the embodiment, the antibacterial composition provided by the invention treats and kills drug-resistant bacteria by combining natural traditional Chinese medicine extract shikimic acid with antibiotics, so that the use amount of the antibiotics is obviously reduced, the drug-resistant bacteria are killed, meanwhile, the antibacterial composition has no obvious influence on organs and tissues such as liver, spleen and kidney, has few side effects and high safety, and can obviously inhibit and kill methicillin-resistant staphylococcus aureus (MRSA) in a short time by combining medicines at a proper concentration.
Although the foregoing embodiments have been described in some, but not all, embodiments of the invention, it should be understood that other embodiments may be devised in accordance with the present embodiments without departing from the spirit and scope of the invention.
Claims (10)
1. An antibacterial composition is characterized by comprising the following components in parts by weight: 8-32 parts of antibiotics and 312-625 parts of shikimic acid.
2. The antimicrobial composition of claim 1, wherein the antibiotic comprises a β -lactam antibiotic.
3. The antimicrobial composition of claim 2, wherein the β -lactam antibiotic comprises penicillin, ampicillin, amoxicillin, or ceftiofur.
4. An antimicrobial composition according to claim 3, wherein the ceftiofur comprises ceftiofur sodium.
5. A method for preparing the antibacterial composition according to any one of claims 1 to 4, comprising: mixing the antibiotic and shikimic acid to obtain the antibacterial composition.
6. Use of an antibacterial composition according to any one of claims 1 to 4 or an antibacterial composition obtained by the preparation method according to claim 5 for the preparation of an antibacterial drug.
7. The use of claim 6, wherein the bacteria comprise drug-resistant bacteria.
8. The use according to claim 7, wherein the resistant bacteria comprise staphylococcus aureus and/or escherichia coli.
9. The use according to claim 8, wherein the staphylococcus aureus comprises methicillin-resistant staphylococcus aureus.
10. An antibacterial agent characterized in that the active ingredient of the antibacterial agent comprises the antibacterial composition according to any one of claims 1 to 4 or the antibacterial composition obtained by the production method according to claim 5.
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| CN102633629A (en) * | 2012-04-01 | 2012-08-15 | 浙江师范大学 | Synthesis method of shikimic acid |
| US20150141357A1 (en) * | 2013-11-20 | 2015-05-21 | National Tsing Hua University | Shikimate pathway inhibitors and the use thereof |
| CN105132387A (en) * | 2008-12-22 | 2015-12-09 | 绿光生物科学公司 | Compositions and methods for the production of a compound |
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| CN102633629A (en) * | 2012-04-01 | 2012-08-15 | 浙江师范大学 | Synthesis method of shikimic acid |
| US20150141357A1 (en) * | 2013-11-20 | 2015-05-21 | National Tsing Hua University | Shikimate pathway inhibitors and the use thereof |
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