CN115671313A - Column aromatic hydrocarbon compound, preparation method and application thereof - Google Patents
Column aromatic hydrocarbon compound, preparation method and application thereof Download PDFInfo
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Abstract
The invention belongs to the technical field of medicines, and relates to a column aromatic hydrocarbon compound, a preparation method and application thereof. The compound has good anti-biofilm activity, synergistically improves the inhibition effect of the medicament on bacteria, and has obvious treatment effect on bacterial wound infection. The complex has simple forming conditions, good water solubility and biocompatibility, is suitable for biological medicines, and has great application prospect in anti-infection treatment.
Description
Technical Field
The invention belongs to the technical field of biomedicine, and particularly relates to a column aromatic compound, a preparation method and application thereof.
Background
With increasing morbidity and mortality, bacterial infections have become a serious health problem in the world. Pathogenic bacteria can invade host cells and release toxins, and untimely treatment can result in amputation, septicemia and the like, and even death. Currently, antibiotics remain the primary drugs in the clinic for the treatment of bacterial infections. However, the therapeutic efficacy of conventional antibiotics is becoming increasingly poor due to the continuing development of bacterial resistance and the barrier of bacteria to penetration of antibacterial agents. Establishing a physical or chemical barrier is a key strategy for pathogenic bacteria to self-protect, fight host immune clearance, and attack by antibiotics. Biofilms are one of the important protective barriers for bacteria. It is mainly composed of extracellular polymers of polysaccharide, protein, nucleotide and phospholipid. Bacteria can irreversibly adhere to the surface of human tissue, and can multiply and proliferate to gradually form a biological film, which causes serious bacterial chronic infection at the focus. The extracellular polymers provide protection for bacterial cells and the net negative charge on their surface can interact with antibiotics to limit their penetration through biofilms to kill bacteria in the membrane. And if the microorganisms under the biofilm are only killed and the biofilm cannot be removed, planktonic bacteria can be continuously adhered to the biofilm, resulting in continuous infection. A single treatment regimen rarely achieves both biofilm disruption and bacterial inhibition.
In response to this problem, macrocyclic scaffolds have great potential in terms of antibacterial activity. The pillared arene is a novel macrocyclic compound, has a nano-scale cavity structure, is easy to modify, can efficiently identify various objects through supermolecule action, and shows wide application prospects. The development of the cationic type pillar aromatic medicine with better antibacterial activity has important significance.
Disclosure of Invention
In order to improve the technical problem, the invention provides a compound, which comprises cationic type column aromatic hydrocarbon and drug molecules;
according to an embodiment of the present invention, the complex is constructed by intermolecular supramolecular interaction between the cationic type pillar aromatic hydrocarbon and the drug molecule.
According to an embodiment of the present invention, the cationic type pillar arene is selected from cationic type pillar arenes having biofilm inhibiting activity;
according to an embodiment of the invention, the drug is an antibacterial drug, for example selected from ciprofloxacin, vancomycin hydrochloride, cefotiam, teicoplanin, oxacillin, etimicin, lauric acid or azelaic acid; azelaic acid is preferred.
According to an embodiment of the present invention, the cationic type pillar arene has a structure as shown in the following formula I,
wherein n is selected from 5, 6, 7, 8, 9 or 10;
R 1 、R 2 、R 3 the same or different, independently from each other, are selected from H, C 1-6 Alkyl, or R 1 、R 2 、R 3 Together with the attached N atom, form a 5-8 membered heteroaryl or 5-8 membered heterocyclyl, optionally containing 1,2 or 3 heteroatoms independently selected from N, O or S; the heteroaryl group may be selected from pyrazolyl, pyridinyl, preferably pyrazol-1-yl, pyridin-1-yl; the heterocyclic radical is preferably pyrrolyl or piperidinyl, preferably pyrrol-1-yl or piperidin-1-yl;
y is selected from halogen, such as F, cl, br or I;
a is selected from 0, 1,2, 3, 4, 5, 6, 7, 8 or 9;
according to an embodiment of the invention, R is selected from the structures shown below:
wherein a and Y have the definitions described above.
According to an embodiment of the present invention, the cationic type column arene is a water soluble column [5] arene (WP 5A) of a full ammonium salt, the structure of which is shown in formula II below:
y has the definition described above, preferably Br.
According to a preferred embodiment of the present invention, the cationic type pillar arene complex is a complex formed by a compound of formula II (WP 5A) and azelaic acid (AzA).
The invention also provides a preparation method of the compound, which comprises the following steps:
dissolving the cationic type column aromatic hydrocarbon and the drug molecules in a benign solvent and mixing to obtain the compound;
according to an embodiment of the present invention, the molar ratio of the cationic type pillar arene to the drug molecule is between 0.1 and 10; preferably 0.5 to 5; more preferably 1;
according to an embodiment of the invention, the cationic type column arene is WP5A;
according to an embodiment of the present invention, the benign solvent is selected from the group consisting of water, a buffer solution (e.g., phosphoric acid buffer solution, carbonic acid buffer solution, etc.), methanol, ethanol, isopropanol, or any mixture solution thereof;
according to an embodiment of the invention, the molar volume ratio of said cationic type column arene to said benign solvent is from 0.05 to 5mol/L, for example from 0.1 to 2mol/L, such as 0.2mol/L, 0.4mol/L, 0.6mol/L, 0.8mol/L, 1mol/L;
according to an embodiment of the invention, the mixing time is 1 to 120 minutes, such as 10 to 60 minutes, preferably 20 to 30 minutes;
according to an embodiment of the invention, the temperature at the time of mixing is 20 to 80 ℃, such as 30 to 60 ℃, preferably 40 to 60 ℃;
according to an embodiment of the present invention, the preparation method further comprises freeze-drying or vacuum-drying the mixed reaction solution under reduced pressure to obtain the compound.
According to a preferred embodiment of the invention, the preparation process comprises the following steps:
directly dissolving a mixture of WP5A and AzA in benign solvent, and ultrasonically shaking for a period of time (preferably 20-30 minutes) at 30-60 ℃ (preferably 40-60 ℃) until AzA is completely dissolved, and then freeze-drying or vacuum-drying the solution of the mixture under reduced pressure to obtain the compound.
The invention also provides an application of the compound in preparing antibacterial or anti-biofilm medicaments.
According to an embodiment of the invention, the bacteria are selected from staphylococcus aureus, pseudomonas aeruginosa, escherichia coli, bacillus subtilis, staphylococcus epidermidis, streptococcus or bacillus; preferably, staphylococcus aureus.
The invention also provides a method of treating a bacterial infection comprising administering to a patient a therapeutically effective amount of the complex, thereby treating the bacterial infection.
The invention also provides a method of combating, killing or inhibiting bacteria, which comprises administering to a patient a therapeutically effective amount of said complex.
The invention also provides an antibacterial or anti-biofilm pharmaceutical composition comprising at least one of said complexes.
According to an embodiment of the invention, the pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier.
According to an embodiment of the invention, the bacteria may be bacteria selected from staphylococcus aureus, pseudomonas aeruginosa, escherichia coli, bacillus subtilis, staphylococcus epidermidis, streptococcus or bacillus; preferably, staphylococcus aureus.
Advantageous effects
The compound of the cationic type column aromatic hydrocarbon and the drug molecules prepared by the invention has good biocompatibility, can effectively keep the activity of a main body biological membrane, and simultaneously synergistically enhances the antibacterial effect; in the aspect of wound treatment of bacterial infection, the preparation can effectively relieve inflammatory reaction at a focus, promote wound recovery and reduce bacterial load at an affected part. The compound of the invention has simple preparation and mild reaction condition, and is suitable for industrial production.
Drawings
FIG. 1: relative cell viability of HaCaT cells at different concentrations of WP5A.
FIG. 2: of WP5A, azA and composites thereof 1 H-NMR spectrum (D) 2 O,5 mM); wherein (a) AzA; (b) AzA/WP5A; (c) WP5A.
FIG. 3: azA, WP5A and AzA/WP5A complex inhibit biofilm production by Staphylococcus aureus.
FIG. 4: inhibition of Staphylococcus aureus by AzA, WP5A and AzA/WP5A complexes.
FIG. 5: wound healing in mice after bacterial infection.
FIG. 6: relative bacterial colony numbers in mouse wounds following bacterial infection.
FIG. 7: pathological section results of mouse skin tissue after bacterial infection.
Definition and description of terms
Unless otherwise indicated, the definitions of groups and terms described in the specification and claims of the present application, including definitions thereof as examples, exemplary definitions, preferred definitions, definitions described in tables, definitions of specific compounds in the examples, and the like, may be arbitrarily combined and coupled with each other. Such combinations and definitions of groups and structures of compounds after combination are to be understood as being within the scope of the present description and/or claims.
The term "halogen" denotes fluorine, chlorine, bromine and iodine.
The term "C 1-6 Alkyl "is understood to mean a straight-chain or branched saturated monovalent hydrocarbon radical having from 1 to 6 carbon atoms. The alkyl group is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl, or the like or isomers thereof.
The term "5-8 membered heterocyclyl" refers to a saturated or unsaturated non-aromatic ring or ring system, for example, which is a 5-, 6-, 7-, or 8-membered monocyclic or 8-membered bicyclic (e.g., fused, bridged, spiro) ring, and contains at least one, e.g., 1,2, 3, or more heteroatoms selected from O, S and N, wherein N and S may also be optionally oxidized to various oxidation states,to form nitroxides, -S (O) -or-S (O) 2 -state of (c). Preferably, the heterocyclic group may be selected from "5-6 membered heterocyclic group". The term "5-6 membered heterocyclyl" means a saturated or unsaturated non-aromatic ring or ring system and contains at least one heteroatom selected from O, S and N. The heterocyclic group may be attached to the rest of the molecule through any of the carbon atoms or nitrogen atom (if present). The heterocyclic group may include fused or bridged rings as well as spiro rings. The heterocyclic group may be selected from 4-membered rings, such as azetidinyl; 5-membered rings such as pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl; or a 6-membered ring, such as piperidinyl, morpholinyl, thiomorpholinyl, or piperazinyl; or a 7-membered ring such as diazepanyl.
The term "5-8 membered heteroaryl" is understood to include such monovalent monocyclic or bicyclic (e.g. fused, bridged, spiro) aromatic ring systems: having 5, 6, 7 or 8 ring atoms and comprising 1,2 or 3 heteroatoms independently selected from N, O and S, e.g., "5-6 membered heteroaryl. The term "5-6 membered heteroaryl" is understood to include such monovalent monocyclic aromatic ring systems: which has 5 or 6 ring atoms and which contains 1,2 or 3 heteroatoms independently selected from N, O and S and, in addition, can be benzo-fused in each case. For example, from pyrrolyl, imidazolyl, pyrazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl.
The term "supramolecular interaction" refers to an interaction between molecules, such as van der waals forces, hydrogen bonding, hydrophobic interactions, electrostatic interactions, pi-pi stacking, and the like, or a plurality thereof. Intermolecular supramolecular interactions are the basis for supramolecular chemistry research.
The term "recognition" is the process by which two or more molecules interact through non-covalent bonding to produce a particular function.
Detailed Description
The technical solution of the present invention will be further described in detail with reference to specific embodiments. It is to be understood that the following examples are only illustrative and explanatory of the present invention and should not be construed as limiting the scope of the present invention. All the techniques realized based on the above-mentioned contents of the present invention are covered in the protection scope of the present invention.
Unless otherwise specified, the raw materials and reagents used in the following examples are all commercially available products or can be prepared by known methods. Y in WP5A used in the examples is bromide.
Example 1: cytotoxicity assay for WP5A
1. Experimental sample
WP5A (Y is bromide), prepared with reference to j.am. Chem. Soc.2016,138, 754-757.
Human immortalized epidermal cells (HaCaT cells) were supplied by the beijing concerted cell bank.
2. Experimental method
MTT method: DMEM medium for HaCaT cells (containing 10% FBS,1% penicillin/streptomycin) at 5% CO 2 And culturing at a constant temperature of 37 ℃. Collecting cells grown in log phase, adjusting the cell suspension concentration, inoculating the cell suspension into a 96-well plate, plating to a cell density of about 10000/well, 100. Mu.L cell suspension per well, and reducing the CO content to 5% 2 Incubation was carried out at 37 ℃ for 48 hours, adherent growth of cells was observed under a microscope, and 10. Mu.L of WP5A was added to the plate at various concentrations. Add 10. Mu.L of the same concentration of WP5A to each well and finally PBS as a blank. After 5 minutes of gentle shaking on a shaker, the plates were placed at 5% CO 2 And a constant temperature incubator at 37 ℃. After 48 hours, the plates were removed, 10. Mu.L of MTT (5 mg/mL) solution was added to each well under aseptic conditions, incubation was continued for half an hour, the incubation was terminated, and the culture solution in the wells was aspirated. Next, 100. Mu.L of DMSO was added to each well, and the mixture was placed on a shaker and shaken at a low speed for 10 minutes to dissolve the purple crystals sufficiently. And detecting the light absorption value of each hole at 490nm of a full-automatic enzyme labeling instrument.
3. Results of the experiment
As shown in fig. 1. The result shows that WP5A has no obvious toxicity to HaCaT cells and has good biological safety.
Example 2: preparation and characterization of AzA/WP5A composite
1. Experimental sample
WP5A (Y is bromide), prepared with reference to j.am. Chem. Soc.2016,138, 754-757.
Azelaic acid is commercially available from Beijing An Naiji chemical technology, inc.
2. Experimental methods
A mixture of WP5A (2mM, 4.8g) and AzA (2mM, 0.37g) was dissolved directly in water (5mL, 40 ℃ -60 ℃) with sonication for 30 minutes until AzA was completely dissolved, and then the solution of the mixture was freeze-dried or vacuum-dried under reduced pressure to give AzA/WP5A complex (white solid). Guest AzA alone, host WP5A and composite at D 2 Of O 1 H-NMR is shown in FIG. 2.
As is evident from FIG. 2, azA H is shown after AzA drug is entrapped in WP5A c And H d The proton peak exhibits a significant high field shift. The chemical shift change values are respectively delta (3) = -2.75 and delta (4) = -3.48, which shows that AzA enters the cavity of WP5A and is shielded by a benzene ring, so that the nuclear magnetic signal peak of AzA moves to a high field. Meanwhile, since the host molecule WP5A is affected by the unshielding effect, the chemical shift of the hydrogen atom thereon moves to a low field. These results indicate that AzA penetrated into the cavity of WP5A.
Further, the bond constant (3.40. + -. 0.20). Times.10 of WP5A and azelaic acid was determined 4 M -1 。
Example 3: evaluation of AzA/WP5A complex on inhibition of staphylococcus aureus and biofilm thereof
1. Experimental sample
AzA/WP5A composite: example 2.
Staphylococcus aureus (ATCC 25922) glycerol stocks were purchased from Aobang Biotech, inc., zhongsheng, beijing.
2. Experimental method
Preparation of nutrient broth: 3g of beef powder, 10g of peptone, 10g of agar powder and 5g of sodium chloride are accurately weighed, dissolved in 1L of distilled water, adjusted to pH 7.4 with NaOH, placed on a heater, stirred, heated and boiled for 2 hours. Pouring into a wide-mouth bottle while hot, wrapping the bottle mouth with kraft paper, sterilizing in an autoclave for 15 min, covering with a cover, cooling, and storing in a refrigerator at 4 deg.C.
Biofilm inhibition experiments: quickly thawing a staphylococcus aureus glycerol frozen stock solution in a water bath kettle, diluting the bacterial solution with nutrient broth according to a ratio of 1 6 CFU·mL -1 And (5) standby. Sample solutions at 400 μ M were prepared using nutrient broth, and serial concentrations were diluted in a double dilution method in 96-well plates, each concentration being in parallel with 5 replicate wells, each replicate well being 100 μ L of solution. Then 10 mul of diluted bacterial liquid is added, and the mixture is kept stand and cultured for 24 hours at the constant temperature of 37 ℃ to form a biological membrane. The culture medium in the well plate was aspirated and washed three times with 200. Mu.L of double distilled water. Add 100. Mu.L of methanol to each well, fix for 10 minutes, remove the methanol by suction, and air-dry naturally. Then 100 μ L of 0.4% crystal violet solution was added to each well, stained for 15 minutes at room temperature, followed by washing excess dye with clear water, inverting the plate on filter paper to remove residual water, and dried at room temperature. After completely drying, adding 100 μ L of 33% glacial acetic acid solution into each well, shaking the plate at room temperature for 15 min to fully release the dye, detecting the absorbance of each well at 600nm of a full-automatic enzyme standard instrument to obtain the minimum concentration (MBIC) of the antibacterial agent for inhibiting the formation of more than 50% of biofilm in the culture medium 50 )。
Bacterial inhibition experiments: 24mM AzA solution, WP5A solution and complex sample solution were prepared in nutrient broth and serial concentrations were diluted in a double dilution method in 96-well plates with each concentration being in parallel with 5 replicate wells with 100. Mu.L of solution per replicate well. Then 10. Mu.L of diluted bacterial suspension was added to each well, and the culture was continued overnight in a constant temperature shaker at 37 ℃. The Minimal Inhibitory Concentration (MIC) was directly observed. (MIC is defined as the lowest concentration of drug that the bacteria cannot grow under visual observation)
3. Results of the experiment
As shown in figures 3 and 4, the compound has a dose-effect relationship, the concentration of the drug which can inhibit 50% of Staphylococcus aureus biofilm formation by the compound is 6.25 mu M, the inhibitory activity of the compound on the main body biofilm is not obviously influenced, the antibacterial activity of the compound can be obviously improved, and the MIC is 0.38mM.
Example 4: treatment experiment of AzA/WP5A complex on bacterial infection of mouse wound
1. Experimental sample
AzA/WP5A composite: example 2 was prepared.
SPF-grade Kunming mice were purchased from Stess Bei Fu (Beijing) Biotechnology, inc.
2. Experimental methods
5% chloral hydrate is prepared before the experiment, and the drug is administrated to the anesthetized mice by intraperitoneal injection according to the dosage of 50 mg/kg. Mouse hair was removed from the back of the mouse with a razor, and a circular area with a diameter of 7mm was marked on the skin with a marker pen and cut. Mice not infected with staphylococcus aureus were set as normal group (Un-inf group), and infected mice were randomly divided into four groups, (1) PBS; (2) AzA; (3) WP5A; (4) AzA/WP5A, 4 per group. After 24 hours of infection, treatment was performed every other day with PBS, azA (1 mM), WP5A (1 mM), azA/WP5A (1 mM), respectively. PBS group served as negative control group. The wound healing and body weight of the mice were recorded daily and the size of the wound was measured with a vernier caliper. On day 9 post-contamination, the wound tissue of the mice was cut and mixed well with sterile PBS, diluted with appropriate dilution factors, and the number of bacteria in the wound was determined by plate coating.
3. Results of the experiment
As shown in FIGS. 5 and 6, the wounds recovered slowly in the PBS group, and the wound size was 29.35. + -. 4.88mm on day nine 2 Accompanied by pus and red swelling. 5363 the wound recovery was significantly accelerated and statistically different in the AzA/WP5A treated group. On day 9, the mean wound area was reduced to 5.40. + -. 2.17mm 2 Mean wound area (5.92. + -. 1.42 mm) of near uninfected group 2 ). The bacteria in the wound were quantitatively determined by plate coating method, and the number of staphylococcus aureus colonies in the complex group was only 5.75% of that in the PBS group.
The skin of a bacterium-infected area marked on the back of a mouse is cut by an ophthalmic surgery, then the skin is put into a 4% paraformaldehyde solution for fixation, after 24 hours of fixation, skin sections are prepared and dyed according to the standard of a pathological operation method, and then the prepared skin pathological sections are put into a microscope objective table for observing the pathological sections. The results are shown in FIG. 7, where the PBS group had unclear cytoplasmic boundaries and significant inflammatory cell infiltration, while the AzA/WP5A group treated infected tissue returned to normal histological morphology. The staining results of IL-6 and TNF-alpha show that the PBS group infected wound tissues present a large number of positive signals, the expression levels of IL-6 and TNF-alpha are higher, the inflammatory reaction of mice is serious, and the expression levels of IL-6 and TNF-alpha of infected wounds are not obviously different from those of uninfected groups after the mice are treated by AzA/WP5A compound. These results demonstrate that the complex of the present invention can promote wound healing, relieve the inflammatory reaction of bacterial infection and reduce the bacterial load at the focus, and has obvious therapeutic effect on bacterial infection diseases.
The embodiments of the present invention have been described above by way of example. It should be understood that the scope of the present invention is not limited to the above embodiments. Any modification, equivalent replacement, improvement or the like made by those skilled in the art within the spirit and principle of the present invention should be included in the protection scope of the claims of the present application.
Claims (10)
1. A complex comprising a cationic type pillar arene and a drug molecule;
the cationic type column arene is selected from cationic type column arene with biomembrane inhibiting activity;
the drug is an antibacterial drug, such as ciprofloxacin, vancomycin hydrochloride, cefotiam, teicoplanin, oxacillin, etimicin, lauric acid or azelaic acid; azelaic acid is preferred.
2. The complex of claim 1, wherein the complex is constructed from the cationic type of the pillar arene and a drug molecule through intermolecular supramolecular interactions.
3. The complex according to claim 1 or 2, wherein the cationic type of pillar arene has a structure as shown in formula I,
wherein n is selected from 5, 6, 7, 8, 9 or 10;
R 1 、R 2 、R 3 identical or different, independently of one another, from H, C 1-6 Alkyl, or R 1 、R 2 、R 3 Together with the attached N atom, form a 5-8 membered heteroaryl or 5-8 membered heterocyclyl, optionally containing 1,2 or 3 heteroatoms independently selected from N, O or S; the heteroaryl group may be selected from pyrazolyl, pyridinyl, preferably pyrazol-1-yl, pyridin-1-yl; the heterocyclic radical is preferably pyrrolyl or piperidinyl, preferably pyrrol-1-yl or piperidin-1-yl;
y is selected from halogen, such as F, cl, br or I;
a is selected from 0, 1,2, 3, 4, 5, 6, 7, 8 or 9.
6. The complex of any one of claims 1-5, wherein the complex is formed between a compound of formula II (WP 5A) and azelaic acid (AzA).
7. A method for preparing a complex as claimed in any one of claims 1 to 6, comprising the steps of:
dissolving the cationic type pillar arene and the drug molecules in a benign solvent and mixing to obtain the compound;
preferably, the molar ratio of the cationic type pillar aromatic hydrocarbon to the drug molecule is 0.1-10; preferably 0.5 to 5; more preferably 1;
preferably, the cationic type column arene is WP5A;
preferably, the benign solvent is selected from water, a buffer solution (e.g., phosphoric acid buffer solution, carbonic acid buffer solution, etc.), methanol, ethanol, isopropanol or any mixture thereof;
preferably, the molar volume ratio of the cationic type column aromatic hydrocarbon to the benign solvent is 0.05 to 5mol/L, such as 0.1 to 2mol/L;
preferably, the preparation method further comprises freeze drying or vacuum drying the mixed reaction solution under reduced pressure to obtain the compound.
8. The method of claim 7, comprising the steps of:
directly dissolving a mixture of WP5A and AzA in benign solvent, and ultrasonically shaking for a period of time (preferably 20-30 minutes) at 30-60 ℃ (preferably 40-60 ℃) until AzA is completely dissolved, and then freeze-drying or vacuum-drying the solution of the mixture under reduced pressure to obtain the compound.
9. Use of a complex according to any one of claims 1 to 6 for the preparation of an antibacterial or anti-biofilm agent;
preferably, the bacteria are selected from staphylococcus aureus, pseudomonas aeruginosa, escherichia coli, bacillus subtilis, staphylococcus epidermidis, streptococcus or bacillus; preferably, staphylococcus aureus.
10. An antibacterial or anti-biofilm pharmaceutical composition comprising at least one of the complexes of any one of claims 1-6;
preferably, the bacteria may be bacteria selected from staphylococcus aureus, pseudomonas aeruginosa, escherichia coli, bacillus subtilis, staphylococcus epidermidis, streptococcus or bacillus; preferably, staphylococcus aureus.
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