CN113336675B - Antibacterial guanidine oligomer with anti-drug resistance and preparation method and application thereof - Google Patents

Antibacterial guanidine oligomer with anti-drug resistance and preparation method and application thereof Download PDF

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CN113336675B
CN113336675B CN202110400321.0A CN202110400321A CN113336675B CN 113336675 B CN113336675 B CN 113336675B CN 202110400321 A CN202110400321 A CN 202110400321A CN 113336675 B CN113336675 B CN 113336675B
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guanidine
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冯欣欣
白玉罡
陈智勇
陈亚杰
周彩玲
徐扬帆
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Abstract

The invention discloses an antibacterial guanidine oligomer with drug resistance, a preparation method and application thereof in the field of materials. The structure disclosed by the invention has a dual antibacterial mechanism of destroying cell membranes and combining with chromosomal DNA, has the characteristics of quick sterilization and drug resistance, and shows broad antibacterial spectrum. In addition, the structure has low toxicity to blood cells and high safety in blood. Meanwhile, the structure can be applied to materials, the guanidine oligomer is modified on the surface of the materials, the modified materials have an antibacterial function, the modified materials are further manufactured into devices in a certain shape, and the devices also have the antibacterial function and can quickly and efficiently kill various pathogenic bacteria.

Description

Antibacterial guanidine oligomer with anti-drug resistance and preparation method and application thereof
Technical Field
The invention relates to the field of pharmaceutical and chemical materials, in particular to an antibacterial guanidine oligomer with drug resistance and a preparation method and application thereof.
Background
The microbial contamination of the surfaces of medical materials, food materials and other materials in the field of materials has become a common and serious problem, the development of the high-efficiency antibacterial agent for endowing the surfaces of the materials with antibacterial capability has become an urgent need of the industry, and recently, the concept of the anti-drug-resistance antibacterial agent is established, and the aim of solving the microbial contamination problem of the materials is to introduce the antibacterial agent into the materials.
The anti-drug resistant antimicrobial incorporated into the material should have the following characteristics: 1) has good killing effect on pathogens with multi-drug resistance, has good killing effect on various pathogenic bacteria, and has better antibacterial broad spectrum. 2) Can effectively kill drug-resistant bacteria in the using process, and the rate of drug resistance of the bacteria to the drug-resistant bacteria is low. 3) The material has good compatibility, and the antibacterial agent can be connected to the material or doped into the material through chemical reaction. It is well known that the root cause of antibiotic resistance is mutation of its target, rendering drugs of various mechanisms of action ineffective. Thus, if a drug can be targeted to multiple targets, or its target involves a complex biological process, the probability of developing drug resistance will be greatly reduced. Compounds of this type of antimicrobial polymers meet the concept of resistance to drugs. The main action mechanism of the antibacterial polymer is to destroy cell membranes, and the biosynthesis of the cell membranes relates to a complex biological process, so that the antibacterial polymer has the characteristics of low drug resistance generation rate and resistance to multi-drug resistant bacteria, and meets the requirements of a drug resistant antibacterial agent. The antibacterial agent with high-efficiency sterilization effect and low drug resistance generation rate is connected into the material, so that the problems of multiple bacteria resistance and drug resistance of the material can be solved.
Disclosure of Invention
In order to solve the problems, the invention discloses an antibacterial guanidine oligomer with drug resistance, a preparation method and application thereof.
An antimicrobial guanidine oligomer having resistance to drugs, the guanidine oligomer having the formula:
Figure BDA0003020170210000011
wherein n is more than or equal to 5 and less than or equal to 8;
wherein the molecular formula of R comprises any one of formula (I), formula (II), formula (III), formula (IV) and formula (V); r1 has a formula including any one of formula (I), formula (II), formula (III), formula (IV), formula (V) (VI), formula (VII), formula (VIII), (IX), (X) and (XI);
Figure BDA0003020170210000012
Figure BDA0003020170210000021
further wherein R is of formula (II) and R1 is of formula (IX), R is of formula (III) and R1 is any one of formulae (VII), (IX), (X), (XI), R is of formula (IV) and R1 is of formula (I), (III), (IV), (VII), (VIII), (IX), (X), (XI), R is of formula (I) and R1 is of formula (I), (III), (VI), (VII), (VIII), (IX), (X), (XI), R is of formula (V) and R1 is of formula (III), (IV), (V), (VI), (IX), (X), (XI).
A preparation method for synthesizing an anti-drug resistant antibacterial guanidine oligomer comprises the following steps:
s1: preparing a dimercaptoiodoiminosalt monomer having the formula;
Figure BDA0003020170210000022
s2: reacting the dimethylsulfydryl iodinated imido salt monomer with H 2 N-R 1 -NH 2 Reacting anhydrous N, N-dimethylformamide DMF and N, N-diisopropylethylamine DIPEA to obtain the guanidine oligomer;
wherein the molecular formula of R in the dimercaptoiodoiminosalt monomer comprises any one of a formula (I), a formula (II), a formula (III), a formula (IV) and a formula (V); r is 1 The formula (VI) includes any one of formula (I), formula (II), formula (III), formula (IV), formula (V) (VI), formula (VII), formula (VIII), (IX), (X) and (XI);
Figure BDA0003020170210000023
optionally, the step S1 includes the following steps: s11: weighing H 2 N-R-NH 2 And benzoyl isothiocyanate are added, dichloromethane is added to be uniformly mixed, a mixture is obtained through stirring, and the mixture is filtered and washed to obtain a dibenzoyl formamide dithiourea compound for the next reaction; s12: weighing the dibenzoamide dithiourea compound obtained in S11, adding methanol, uniformly mixing, then adding a sodium hydroxide aqueous solution, stirring to obtain a mixture, and filtering and washing the mixture to obtain a dithiourea compound for the next reaction; s13: weighing the dithiourea compound obtained in the step S12 and methyl iodide, adding absolute ethyl alcohol, uniformly mixing, stirring to obtain a mixture, and filtering and washing the mixture to obtain the white solid of the dimercapto imino iodide salt monomer.
Optionally, the step S2 includes the following steps: s21: weighing dimercapto imino iodide monomer and H 2 N-R 1 -NH 2 Uniformly mixing the mixture and anhydrous N, N-dimethylformamide DMF, adding N, N-diisopropylethylamine DIPEA, and stirring to obtain a mixture; s22: adjusting pH of the mixture in S21 to 1-2, intercepting to obtain substance with molecular weight of more than 1.5KDa, freeze drying to obtain white solidAn oligomer.
The invention also discloses an antibacterial material modified by the oligomer, wherein the guanidine oligomer is used for the internal and surface modification of the material, the material and the surface of the material modified by the guanidine oligomer have antibacterial performance, and the antibacterial types comprise bacillus subtilis, escherichia coli, enterococcus faecalis, staphylococcus aureus, klebsiella pneumoniae, acinetobacter baumannii, pseudomonas aeruginosa and enterobacter cloacae.
Furthermore, the invention also discloses the application of the oligomer, the guanidine oligomer is used for antibiosis, and the antibacterial types of the guanidine oligomer comprise bacillus subtilis, escherichia coli, enterococcus faecalis, staphylococcus aureus, klebsiella pneumoniae, acinetobacter baumannii, pseudomonas aeruginosa and enterobacter cloacae.
The structure disclosed by the invention has a dual antibacterial mechanism of destroying cell membranes and combining with chromosome DNA, has the characteristics of quick sterilization and drug resistance, and shows broad antibacterial spectrum. Meanwhile, the structure has very low toxicity to blood cells and higher therapeutic index. In addition, the structure can be added into the interior and the surface of the material in a chemical combination reaction fixing or doping mode, so that the material has an antibacterial function.
Drawings
FIG. 1 is a schematic diagram of the reaction of the present invention;
FIG. 2 is a diagram of a flow test that C3 has a strong membrane rupture capability;
fig. 3 is an SEM image: the cell membrane surfaces of C3-treated acinetobacter baumannii and staphylococcus aureus are all shrunk to different degrees;
FIG. 4 is a diagram of C3 having the ability to bind bacterial genomic DNA;
FIG. 5 is a distribution diagram of FITC-labeled C3 in E.coli;
FIG. 6 is a graph comparing the rates of resistance development after treatment of E.coli 1464 generations with the sub-minimum inhibitory concentrations of kanamycin and C3, respectively;
FIG. 7 is a reaction scheme of C3 grafting to epsilon-Polycaprolactone (PCL) material surface;
FIG. 8a is a diagram showing the broad-spectrum antibacterial effect of the C3 modified epsilon-Polycaprolactone (PCL) material;
FIG. 8b is a diagram showing the sterilization and recycling effects of the C3 modified epsilon-Polycaprolactone (PCL) material;
FIG. 8C is a chart of the hemolytic toxicity of C3 modified epsilon-Polycaprolactone (PCL) material;
FIG. 9 is a drawing of an antibacterial tube device made of the epsilon-Polycaprolactone (PCL) material modified by C3;
FIG. 10a is a graph showing the bactericidal effect of C3 modified epsilon-Polycaprolactone (PCL) material on buffers containing Staphylococcus aureus (clinical strains), Acinetobacter baumannii (clinical strains), Pseudomonas aeruginosa (clinical strains) and Enterobacter cloacae (clinical strains), respectively, when made into an antibacterial tube device;
FIG. 10b is a diagram showing the bactericidal effect of the antibacterial tube device made of the C3 modified epsilon-Polycaprolactone (PCL) material on blood containing Staphylococcus aureus (clinical strains) or Staphylococcus aureus;
FIGS. 11-1 through 11-55 are hydrogen spectra of 55 compounds of the present invention.
Detailed Description
The technical solution of the present invention is described in detail below by means of specific embodiments and with reference to the attached drawings, and the components or devices in the following embodiments are all general standard components or components known to those skilled in the art, and the structure and principle thereof can be known to those skilled in the art through technical manuals or through routine experiments.
Example one
Through tests, 55 antibacterial guanidine oligomers with broad-spectrum antibacterial property are developed by the invention, and the chemical formula of the oligomers is shown as follows:
Figure BDA0003020170210000041
wherein n is more than or equal to 5 and less than or equal to 8;
wherein the molecular formula of R comprises any one of formula (I), formula (II), formula (III), formula (IV) and formula (V); the formula of R1 includes any one of formula (I), formula (II), formula (III), formula (IV), formula (V) (VI), formula (VII), formula (VIII), (IX), (X) and (XI).
Figure BDA0003020170210000042
For convenience of recording, the molecular formulas of R are respectively D, A, B, C and E which are numbered in sequence as formula (I), formula (II), formula (III), formula (IV) and formula (V); the molecular formula of R1 is formula (I), formula (II), formula (III), formula (IV), formula (V) (VI), formula (VII), formula (VIII), (IX), (X) and (XI) which are numbered as 9, 1, 2, 3, 5, 6, 4, 10, 8, 7 and 11 respectively. Numbering example: when R is formula (III) and R1 is formula (IV), compound number is B3. The antibacterial properties of the 55 compounds are shown in tables 1 and 2; hemolytic toxicity as shown in table 3, table 3 shows that A8, B4, B7, B8, B11, C2, C3, C4, C7, C8, C9, C10, C11, D2, D4, D6, D7, D8, D9, D10, D11, E2, E3, E4, E5, E6, E7, E8, and E11 all have hemolytic concentrations greater than 2048 μ g/mL, and show lower hemolytic toxicity; the hydrogen spectra of the 55 compounds are shown in FIGS. 11-1 to 11-55.
Antibacterial Properties of Table 155 Compounds
Figure BDA0003020170210000043
Figure BDA0003020170210000051
Antibacterial property II of 255 compounds in table
Figure BDA0003020170210000061
Hemolytic toxicity of the 355 Compounds
Figure BDA0003020170210000062
Figure BDA0003020170210000071
Example two
As shown in fig. 1, the invention also discloses a preparation method of the synthetic anti-drug resistant antibacterial guanidine oligomer, which comprises the following steps:
s1: preparing a dimercaptoiodoiminosalt monomer having the formula;
Figure BDA0003020170210000072
s2: reacting the dimercapto-iodinated imido salt monomer with H 2 N-R 1 -NH 2 Reacting anhydrous N, N-dimethylformamide DMF and N, N-diisopropylethylamine DIPEA to obtain the guanidine oligomer;
wherein the molecular formula of R in the dimercaptoimino iodide monomer comprises any one of a formula (I), a formula (II), a formula (III), a formula (IV) and a formula (V); the formula of R1 includes any one of formula (I), formula (II), formula (III), formula (IV), formula (V) (VI), formula (VII), formula (VIII), (IX), (X) and (XI).
Figure BDA0003020170210000073
Figure BDA0003020170210000081
The step S1 includes the following steps:
s11: weighing H 2 N-R-NH 2 And benzoyl isothiocyanate, then adding dichloromethane, uniformly mixing, stirring at room temperature for 24-48h to obtain a mixture, and filtering and washing the mixture to obtain the dibenzoyl formamide dithiourea compound for the next reaction.
S12: weighing the dibenzoyl formamide dithiourea compound obtained in S11, adding methanol, uniformly mixing, then adding an aqueous solution of sodium hydroxide, stirring at room temperature for 24-48h to obtain a mixture, and filtering and washing the mixture to obtain the dithiourea compound for the next reaction.
S13: weighing the dithiourea compound obtained in the step S12 and methyl iodide, adding absolute ethyl alcohol, uniformly mixing, stirring at room temperature for 24-48h to obtain a mixture, and filtering and washing the mixture to obtain the white dimercapto imino iodide monomer solid.
The step S2 includes the following steps:
s21: weighing dimercapto imino iodide monomer and H obtained in S1 2 N-R 1 -NH 2 And anhydrous N, N-dimethylformamide DMF, adding N, N-diisopropylethylamine DIPEA, and stirring at 65 ℃ for 96-144h under the protection of inert gas to obtain a mixture.
S22: and (3) adjusting the pH value of the mixture in the S21 to 1-2, then intercepting to obtain a substance with the molecular weight of more than 1.5KDa, and freeze-drying to obtain a white solid, namely the guanidine oligomer.
Experimental example 1
This experimental example will be described in detail with reference to the compound C3 as an example.
Materials and methods: all reagents were supplied by Acros, TCI (USA), Sigma-Aldrich, Michelin, Adamax et al organic reagents and Bilyunnan Biotech, all used without further purification (among others). Ultrapure water for the experiments was obtained from a Milli-Q purification instrument. The inert gas is nitrogen or argon.
The synthetic synthesis procedure for C3 is shown in fig. 1. Firstly, synthesizing dimercapto iodide imide salt monomer. 1, 4-butanediamine (0.84g,9.5mmol) and benzoyl isothiocyanate (3.25g,20.0mmol) were weighed out, then 100mL of dichloromethane was added and mixed uniformly, stirred at room temperature for 24-48h to obtain a mixture, and the mixture was filtered and washed to obtain a dibenzoyl formamide dithiourea compound for the next reaction. The dibenzoamide dithiourea compound (3.1g,7.5mmol) obtained in the previous step was weighed, 100mL of methanol was added and mixed uniformly, then aqueous sodium hydroxide (5.0M,7.5mL,37.5mmol) was added and stirred at room temperature for 24-48h to obtain a mixture, and the mixture was filtered and washed to obtain the dithiourea compound for the next reaction. The dithiourea compound (1.3g,6.5mmol) obtained in the previous step and methyl iodide (2.33g,16.4mmol) were weighed, 100mL of anhydrous ethanol was added and mixed uniformly, and stirred at room temperature for 24-48 hours to obtain a mixture, and the mixture was filtered and washed to obtain 3.1g of dimercaptoiodoimide salt monomer (butyldimercaptoiodoimide salt monomer) as a white solid.
Weighing dimercaptoiodimide salt monomer (butyl dimercaptoiodimide salt monomer) (0.30g,0.6mmol) and 1, 4-butanediamine (0.05g,0.6mmol), adding 1.0mL of anhydrous N, N-dimethylformamide DMF, uniformly mixing, adding N, N-diisopropylethylamine DIPEA (0.31g,2.4mmol), stirring at 65 ℃ under the protection of inert gas to obtain a mixture, adjusting the pH of the mixture to 1-2, dialyzing in a dialysis bag with the molecular weight cutoff of 1.5kDa for 10 hours, changing water every two hours, and freeze-drying to obtain 0.06g of white solid.
C3 has broad-spectrum antibacterial activity compound C3 was tested for its antibacterial activity against various bacteria (tables 1 and 2). C3 showed good antibacterial activity, and the minimum inhibitory concentration was in the lower range (μ g/mL) for all tests. Besides, the activity of C3 on 5 high-drug-resistant clinical pathogens is tested, and the minimum inhibitory concentration is found to be in a lower range (mu g/mL). The antibacterial activity data show that C3 not only can widely kill various pathogenic bacteria and has good antibacterial broad spectrum, but also can effectively kill various drug-resistant pathogenic bacteria and has anti-drug resistance.
C3 has lower hemolytic toxicity most polymers half hemolytic concentration greater than 2048 μ g/mL (Table 3), wherein C3 half hemolytic concentration greater than 2048 μ g/mL, showed lower hemolytic toxicity. The C3 can effectively kill various pathogenic bacteria and drug-resistant pathogenic bacteria, simultaneously keeps lower hemolytic toxicity, has little damage to blood cells, and indicates that the biocompatibility of the C3 is higher.
Validation of membrane targeting mechanism we assessed the membrane rupture ability of C3 using flow-through experiments. In flow experiments, Propidium Iodide (PI) is used as a fluorescent dye to assess the integrity of bacterial cell membranes. Cultured to stationary phaseAfter centrifugation of E.coli, the medium was discarded, washed three times with PBS, and then resuspended to OD with 100. mu.M PI-containing PBS 600nm The cells were incubated at 37 ℃ for 4h with the addition of C3 at the indicated concentration, 0.1. The samples were analyzed using a BD Accuri C6 Plus flow cytometer. Since Propidium Iodide (PI) can only enter cells with damaged cell membranes, PI can be a good indicator of the integrity of bacterial cell membranes in flow experiments. As shown in FIG. 2, the results indicate that the E.coli treated with C3 has more PI accumulation and thus emits stronger fluorescence. Untreated E.coli showed very low fluorescence.
We further used scanning electron microscopy to demonstrate the membrane rupture ability of C3. As shown in FIG. 3, the C3 treated bacteria showed significant membrane breakage and shrinkage relative to the untreated A.baumannii and S.aureus controls.
Validation of binding to DNA antibacterial mechanism the oligomer was designed based primarily on a dual antibacterial mechanism of membrane targeting and DNA targeting. In addition to the demonstration of the membrane-breaking ability of C3, we also demonstrated that the oligomer has the ability to bind bacterial DNA. Dynamic Light Scattering (DLS) studies showed that C3 all promoted aggregation of E.coli genomic DNA. As shown in FIG. 4, the particle size of the oligomer-DNA complex formed by binding C3 to DNA is much larger than that of C3 and that of DNA, demonstrating that the strong affinity between C3 and DNA can bind to bacterial DNA.
After confirming that C3 has the ability to bind DNA in vitro, we observed its binding to bacterial DNA with fluorescein FITC labeled C3. As shown in FIG. 5, which shows the staining of Escherichia coli bacteria by fluorescein FITC-labeled C3, the staining channel of C3 ("C3"), the staining channel of cell membrane ("FM 4-64") and the staining channel of DNA ("DAPI") can be well combined together, indicating that C3 can bind to the DNA of bacteria in bacteria, further demonstrating the mechanism by which C3 can bind to DNA.
Determination of the rate of resistance development by C3 introduces a dual antibacterial mechanism that reduces the rate at which bacteria develop resistance to compounds. The target of the membrane-targeted antibacterial polymer is the cell membrane, and due to the complex biosynthesis of the cell membrane, drug resistance is generated only when multiple random mutations occur simultaneously and cause changes in the membrane structure. Thus, membrane-targeted polymers are considered a class of antimicrobial compounds with low drug resistance. As a membrane-targeting polymer, C3 also has low drug resistance. In addition, C3 uses bacterial DNA as a secondary target, and therefore bacteria require both membrane and DNA structural mutations to develop resistance to C3. We experimentally determined the rate of C3 resistance, as shown in fig. 6, when escherichia coli is treated repeatedly with kanamycin, the standard antibiotic with the second minimum inhibitory concentration, the strain has resistance mutation, which is shown as the minimum inhibitory concentration to kanamycin is increased continuously, and the minimum inhibitory concentration is increased by 48 times after the bacterium is replicated 1464 generations. In contrast, C3 was almost free of drug resistance under the same conditions. The above results indicate that bacterial resistance is difficult to develop relative to the traditional antibiotic C3.
Experimental example 2
Synthesis of A8: firstly, synthesizing dimercapto iodide imide salt monomer. 1, 8-octanediamine (1.38g,9.5mmol) and benzoyl isothiocyanate (3.25g,20.0mmol) are weighed, then 100mL of dichloromethane is added for uniform mixing, the mixture is stirred at room temperature for 24-48h to obtain a mixture, and the mixture is filtered and washed to obtain a dibenzoyl diamide dithiourea compound for the next reaction. The dibenzoamide dithiourea compound (3.5g,7.5mmol) obtained in the previous step was weighed, 100mL of methanol was added and mixed uniformly, then aqueous sodium hydroxide (5.0M,7.5mL,37.5mmol) was added and stirred at room temperature for 24-48h to obtain a mixture, and the mixture was filtered and washed to obtain the dithiourea compound for the next reaction. The dithiourea compound (1.7 g,6.5mmol) obtained in the previous step and methyl iodide (2.33g,16.4mmol) were weighed, 100mL of anhydrous ethanol was added and mixed uniformly, and stirred at room temperature for 24-48 hours to obtain a mixture, and the mixture was filtered and washed to obtain 3.4g of dimercaptoiodoimide salt monomer (octyldimercaptoiodoimide salt monomer) as a white solid.
Weighing dimercaptoiodized imino salt monomer (butyldimercaptoiodized imino salt monomer) (0.32g,0.6mmol) and N' N-bis (3-aminopropyl) methylamine (0.09g,0.6mmol), adding 1.0mL of anhydrous N, N-dimethylformamide DMF, mixing uniformly, adding N, N-diisopropylethylamine DIPEA (0.31g,2.4mmol), stirring at 65 ℃ under the protection of inert gas to obtain a mixture, adjusting the pH of the mixture to 1-2, dialyzing in a dialysis bag with the molecular weight cutoff of 1.5kDa for 10h, changing water every two hours, and freeze-drying to obtain 0.07g of white solid.
Experimental example 3
Synthesis of B4: firstly, synthesizing dimercapto iodide imide salt monomer. 1, 6-hexanediamine (1.1g,9.5mmol) and benzoyl isothiocyanate (3.25g,20.0mmol) were weighed out and then 100mL of dichloromethane was added and mixed well, and stirred at room temperature for 24-48h to obtain a mixture, which was filtered and washed to obtain a dibenzoyl formamide dithiourea compound for the next reaction. The dibenzoamide dithiourea compound (3.3g,7.5mmol) obtained in the previous step was weighed, 100mL of methanol was added and mixed uniformly, then aqueous sodium hydroxide (5.0M,7.5mL,37.5mmol) was added and stirred at room temperature for 24-48h to obtain a mixture, and the mixture was filtered and washed to obtain the dithiourea compound for the next reaction. The dithiourea compound (1.5g,6.5mmol) obtained in the previous step and methyl iodide (2.33g,16.4mmol) were weighed, 100mL of anhydrous ethanol was added and mixed uniformly, and the mixture was stirred at room temperature for 24 to 48 hours to obtain a mixture, and the mixture was filtered and washed to obtain 3.0g of dimethylmercaptoiminoiodide monomer (hexyldimethylmercaptoiminoiodide monomer) as a white solid.
Weighing dimercaptoiodized imino salt monomer (hexyl dimercaptoiodized imino salt monomer) (0.31g,0.6mmol) and 1, 3-propanediamine (0.04g,0.6mmol), adding 1.0mL of anhydrous N, N-dimethylformamide DMF, uniformly mixing, adding N, N-diisopropylethylamine DIPEA (0.31g,2.4mmol), stirring at 65 ℃ under the protection of inert gas to obtain a mixture, adjusting the pH of the mixture to 1-2, dialyzing in a dialysis bag with the molecular weight cutoff of 1.5kDa for 10 hours, changing water every two hours, and freeze-drying to obtain 0.07g of white solid.
Experimental example 4
Synthesis of D6: firstly, synthesizing dimercapto iodide imide salt monomer. 1, 4-cyclohexyl diamine (1.1g,9.5mmol) and benzoyl isothiocyanate (3.25g,20.0mmol) were weighed out and then 100mL of dichloromethane was added and mixed well, and stirred at room temperature for 24-48h to obtain a mixture, which was filtered and washed to obtain a dibenzoyl formamide dithiourea compound for the next reaction. The dibenzoamide dithiourea compound (3.3g,7.5mmol) obtained in the previous step was weighed, 100mL of methanol was added and mixed uniformly, then aqueous sodium hydroxide (5.0M,7.5mL,37.5mmol) was added and stirred at room temperature for 24-48h to obtain a mixture, and the mixture was filtered and washed to obtain the dithiourea compound for the next reaction. The dithiourea compound (1.5g,6.5mmol) obtained in the previous step and methyl iodide (2.33g,16.4mmol) were weighed, 100mL of anhydrous ethanol was added thereto and mixed uniformly, and the mixture was stirred at room temperature for 24 to 48 hours to obtain a mixture, which was filtered and washed to obtain 3.0g of dimethylmercaptoiminoiodide monomer (cyclohexyldimethylmercaptoiminoiodide monomer) as a white solid.
Weighing dimercaptoiodimide salt monomer (cyclohexyl dimercaptoiodimide salt monomer) (0.31g,0.6mmol) and 1, 3-xylylenediamine (0.08g,0.6mmol), adding 1.0mL of anhydrous N, N-dimethylformamide DMF, uniformly mixing, adding N, N-diisopropylethylamine DIPEA (0.31g,2.4mmol), stirring at 65 ℃ under the protection of inert gas for 120h to obtain a mixture, adjusting the pH of the mixture to 1-2, dialyzing in a dialysis bag with the molecular weight cutoff of 1.5kDa for 10h, changing water every two hours, and freeze-drying to obtain 0.05g of white solid.
Experimental example 5
Synthesis of E7: firstly, synthesizing dimercapto iodide imide salt monomer. 1, 4-xylylenediamine (1.30g,9.5mmol) and benzoyl isothiocyanate (3.25g,20.0mmol) were weighed, then 100mL of dichloromethane was added and mixed uniformly, stirred at room temperature for 24-48h to obtain a mixture, and the mixture was filtered and washed to obtain a dibenzoyl formamide dithiourea compound for the next reaction. The dibenzoamide dithiourea compound (3.5g,7.5mmol) obtained in the previous step was weighed, 100mL of methanol was added and mixed uniformly, then aqueous sodium hydroxide (5.0M,7.5mL,37.5mmol) was added and stirred at room temperature for 24-48h to obtain a mixture, and the mixture was filtered and washed to obtain the dithiourea compound for the next reaction. The dithiourea compound (1.6 g,6.5mmol) obtained in the previous step and methyl iodide (2.33g,16.4mmol) were weighed, 100mL of anhydrous ethanol was added and mixed uniformly, and stirred at room temperature for 24-48 hours to obtain a mixture, and the mixture was filtered and washed to obtain 3.2g of dimethylmercaptyliodiimide monomer (xylylenediamine dimethylmercaptyliodiimide monomer) as a white solid.
Weighing dimercaptoiodized imino salt monomer (xylylenediamine dimercaptoiodized imino salt monomer) (0.32g,0.6mmol) and 2,2' -oxybis (ethylamine) (0.06g,0.6mmol), adding 1.0mL of anhydrous N, N-dimethylformamide DMF, mixing uniformly, adding N, N-diisopropylethylamine DIPEA (0.31g,2.4mmol), stirring at 65 ℃ under the protection of inert gas for 120h to obtain a mixture, adjusting the pH of the mixture to 1-2, dialyzing in a dialysis bag with the molecular weight cutoff of 1.5kDa for 10h, changing water every two hours, and freeze-drying to obtain 0.07g of white solid.
EXAMPLE III
In order to expand the application of the antibacterial guanidine oligomer in material antibiosis, the invention also provides an antibacterial material modified by the oligomer.
Taking oligomer C3 as an example, C3 was modified on the surface of epsilon-Polycaprolactone (PCL) material and the antibacterial ability was measured. The specific method is as follows.
As shown in FIG. 7, the surface of the PCL material is hydrolyzed by aqueous solution of sodium hydroxide, ester bonds on the surface of the PCL material are hydrolyzed to expose carboxyl, then a condensing agent (1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride) is added into the aqueous solution of C3, the PCL material after the hydrolysis treatment of the sodium hydroxide is soaked in the mixture after uniform mixing, the PCL material is taken out after oscillation for 24h, and the PCL material with the surface modified by C3 is obtained by washing with ultrapure water.
Antibacterial property of modified material in order to prove that the material has an antibacterial function after the C3 is connected to the surface of the material, the antibacterial property of the PCL material modified by the C3 is tested. As shown in fig. 8a, the bacteria with a certain concentration is dropped on the surface of the PCL material modified with C3, and the PCL material surface is tested after 1h to completely kill the pathogenic bacteria. Wherein bacillus subtilis, colibacillus, enterococcus faecalis, staphylococcus aureus, klebsiella pneumoniae and enterobacter cloacae can be killed, and the broad-spectrum antibacterial property can be still maintained after C3 is grafted to the material. In addition, we also tested whether the PCL material modified with C3 can be repeatedly sterilized, as shown in fig. 8b, the PCL material subjected to the sterilization test was washed clean, and the above sterilization test was repeated, taking staphylococcus aureus as an example, the PCL material modified with C3 still has good antibacterial activity after 7 repeated tests, which indicates that the material can maintain the sterilization function for a long time after C3 is grafted to the material. In addition to antibacterial ability, we also tested the hemolytic toxicity of PCL material modified with C3 to blood cells, as shown in fig. 8C, the buffer solution containing blood cells was dropped on the surface of PCL material modified with C3, and compared with triton X-100 with one hundred percent hemolytic effect after 1h, only low level of hemolytic toxicity of PCL material was detected, which indicates that the PCL material still maintains low hemolytic toxicity and high safety after C3 is modified on the material.
The antibacterial property of the modified PCL material made into a device proves that the PCL material modified by C3 has good antibacterial property and high safety, so that the application of the PCL material modified by C3 is further expanded. As shown in FIG. 9, the PCL material modified with C3 is bent into a tube with a diameter of 2-4mm, the two tubes are connected to a peristaltic pump, the tube is filled with a buffer solution containing pathogenic bacteria with a certain concentration, the peristaltic pump is started to circulate the bacterial solution in the tube for a certain time, and the number of the residual bacteria is measured. The tubes were tested for their bactericidal effect against staphylococcus aureus (clinical strain), acinetobacter baumannii (clinical strain), pseudomonas aeruginosa (clinical strain) and enterobacter cloacae (clinical strain), respectively, as shown in fig. 10a, the tubes were able to completely kill pathogenic bacteria within a 5min circulation time. Since some pathogenic bacteria such as Staphylococcus aureus have a strong hemolytic effect on blood cells, we also tested the ability of the tube to sterilize Staphylococcus aureus in the blood. The liquid in the tube is replaced by the blood containing staphylococcus aureus (clinical strain) or staphylococcus aureus, and pathogenic bacteria are killed after the liquid circularly flows in the tube for 30min, which shows that the tube also has an antibacterial effect on the pathogenic bacteria in the blood.
In conclusion, the oligomer can simultaneously target cell membranes and nucleic acids of bacteria, retains all antibacterial advantages of the traditional antibacterial polymer due to the dual antibacterial mechanism, has antibacterial broad spectrum and faster sterilization kinetics, and can kill drug-resistant pathogenic bacteria. The oligomer is grafted to the surface of the material to prepare the antibacterial material, so that most of pathogenic bacteria and drug-resistant bacteria can be killed by the material, and the material has stronger antibacterial capability. Furthermore, the oligomer-modified material is made into a device with a certain shape, the device also has antibacterial capability, various practical use environments are simulated, and the made device can also keep a better antibacterial effect.
In the previous description, numerous specific details were set forth in order to provide a thorough understanding of the present invention. The foregoing description is only a preferred embodiment of the invention, which can be embodied in many different forms than described herein, and therefore the invention is not limited to the specific embodiments disclosed above. And that those skilled in the art may, using the methods and techniques disclosed above, make numerous possible variations and modifications to the disclosed embodiments, or modify equivalents thereof, without departing from the scope of the claimed embodiments. Any simple modification, equivalent change and modification of the above embodiments according to the technical essence of the present invention are within the scope of the technical solution of the present invention.

Claims (9)

1. An antibacterial guanidine oligomer having resistance to drug, wherein the guanidine oligomer has the following formula:
Figure FDA0003815146870000011
wherein n is more than or equal to 5 and less than or equal to 8; wherein the molecular formula of R is any one of formula (I), formula (II), formula (III), formula (IV) and formula (V); the molecular formula of R1 is formula (VIII);
Figure FDA0003815146870000012
2. a process for synthesizing the antimicrobial resistant guanidine oligomer of claim 1, comprising the steps of:
s1: preparing a dimercaptoiodoiminosalt monomer having the formula;
Figure FDA0003815146870000013
s2: reacting the dimethylsulfydryl iodinated imido salt monomer with H 2 N-R 1 -NH 2 Reacting anhydrous N, N-dimethylformamide DMF and N, N-diisopropylethylamine DIPEA to obtain the guanidine oligomer;
wherein the molecular formula of R in the dimercaptoiodoiminosalt monomer comprises any one of a formula (I), a formula (II), a formula (III), a formula (IV) and a formula (V); r 1 The molecular formula of (A) is formula (VIII);
Figure FDA0003815146870000014
3. the method of claim 2, wherein the step S1 includes the steps of:
s11: weighing H 2 N-R-NH 2 And benzoyl isothiocyanate are added, dichloromethane is added to be uniformly mixed, a mixture is obtained through stirring, and the mixture is filtered and washed to obtain a dibenzoyl formamide dithiourea compound for the next reaction;
s12: weighing the dibenzoamide dithiourea compound obtained in S11, adding methanol, uniformly mixing, then adding a sodium hydroxide aqueous solution, stirring to obtain a mixture, and filtering and washing the mixture to obtain a dithiourea compound for the next reaction;
s13: and weighing the dithiourea compound obtained in the step S12 and methyl iodide, adding absolute ethyl alcohol, uniformly mixing, stirring to obtain a mixture, and filtering and washing the mixture to obtain the white solid of the dimercapto imidoiodide monomer.
4. The method of claim 2, wherein the step S2 includes the steps of:
s21: weighing dimercapto iodide imino salt monomer and H 2 N-R 1 -NH 2 Uniformly mixing the mixture and anhydrous N, N-dimethylformamide DMF, adding N, N-diisopropylethylamine DIPEA, and stirring to obtain a mixture;
s22: and (3) adjusting the pH value of the mixture in the S21 to 1-2, then intercepting to obtain a substance with the molecular weight of more than 1.5KDa, and freeze-drying to obtain a white solid, namely the guanidine oligomer.
5. The manufacturing method of claim 4, wherein the mixture is obtained in step S21 by stirring for 96-144h under the protection of inert gas.
6. An antimicrobial material modified with the oligomer of claim 1.
7. The antibacterial material of claim 6, wherein the guanidine oligomer is used for internal and surface modification of materials, the guanidine oligomer-modified materials and surfaces of materials have antibacterial performance, and the antibacterial species are Bacillus subtilis, Escherichia coli, enterococcus faecalis, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter cloacae.
8. A method for preparing the antibacterial material of any one of claims 6 to 7, characterized in that the surface of the PCL material is hydrolyzed by sodium hydroxide aqueous solution, ester bonds on the surface of the PCL material are hydrolyzed to expose carboxyl groups, then a condensing agent is added into the guanidine oligomer aqueous solution, after uniform mixing, the PCL material subjected to sodium hydroxide hydrolysis treatment is soaked in the aqueous solution, after 24h of oscillation, the PCL material is taken out, and is washed by ultrapure water to obtain the PCL material with the guanidine oligomer modified on the surface.
9. Use of the resistant, antibacterial guanidine oligomers of claim 1 for the preparation of antibacterial agents against the bacterial species bacillus subtilis, escherichia coli, enterococcus faecalis, staphylococcus aureus, klebsiella pneumoniae, acinetobacter baumannii, pseudomonas aeruginosa, enterobacter cloacae.
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