Antibacterial components

Abstract

The present invention relates to an antimicrobial composition comprising a compound of formula 1, said antimicrobial composition having improved thermal stability and antimicrobial activity.

Description

[Technical Field]

[0001] The present disclosure relates to antimicrobial compositions comprising compounds.

[0002] This application claims the benefit of the filing date of Korean Patent Application No. 10-2022-0175181 filed with the Korean Intellectual Property Office on December 14, 2022, and Korean Patent Application No. 10-2023-0140150 filed with the Korean Intellectual Property Office on October 19, 2023, the entire contents of which are incorporated herein by reference. [Background technology]

[0003] In recent years, there has been a demand for high antibacterial properties in a variety of products, including household goods and hygiene products.

[0004] The required level of antibacterial properties and the requirements for materials to provide antibacterial properties vary depending on the material of the product for which antibacterial properties are required and the final state of use. For example, the properties of the material to provide antibacterial properties and the level of antibacterial properties vary depending on the amount of antibacterial material used in the product and the materials used in combination.

[0005] Therefore, there is a need to develop antibacterial materials that are suitable for use in a variety of products. Summary of the Invention [Problem to be solved by the invention]

[0006] One embodiment of the present invention relates to an antibacterial composition, and more specifically, an object of the present invention is to provide an antibacterial composition containing a quaternary ammonium compound having a specific structure that has hydrophilic and hydrophobic properties and is advantageous for imparting antibacterial properties.

[0007] Furthermore, an object of the antibacterial composition according to one embodiment of the present invention is to ensure heat resistance by including a quaternary ammonium compound containing an anion other than a halogen as a counter ion. [Means for solving the problem]

[0008] One embodiment of the present invention provides an antibacterial composition comprising a compound represented by Formula 1:

[0009] [ka]

[0010] In the above Chemical Formula 1, L1 and L2 are the same or different and each independently represent a direct bond; a substituted or unsubstituted alkylene group having 1 to 4 carbon atoms; or a substituted or unsubstituted arylene group having 6 to 30 carbon atoms; A is hydrogen or a substituted or unsubstituted alkyl group having 1 to 3 carbon atoms; n is an integer from 0 to 4, Among R1 to R3, two groups are the same or different and each independently represents a substituted or unsubstituted alkyl group having 1 to 4 carbon atoms, and the remaining group is a substituted or unsubstituted alkyl group having 3 to 20 carbon atoms; When n is 2 or more, two or more As are the same or different, X - is a hydroxy-based anion, a carbonate-based anion, a citrate-based anion, a cyanate-based anion, a phosphate-based anion, a benzoate-based anion, a sulfonate-based anion, a borate-based anion, a salicylate-based anion, a sulfonamide-based anion, or a sulfonimide-based anion. [Effects of the Invention]

[0011] The antibacterial composition of the present invention contains a compound having a quaternary ammonium structure and a specific anion, which provides high heat resistance while simultaneously ensuring a high level of antibacterial activity. [Brief explanation of the drawings]

[0012] [Figure 1] 1 is a 1H-NMR spectroscopic spectrum of a compound according to one embodiment of the present invention. [Figure 2]1 is a 19F-NMR spectrum of a compound according to one embodiment of the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0013] The present invention will be described in detail below.

[0014] <Antibacterial composition> According to one embodiment of the present invention, there is provided an antibacterial composition comprising a compound represented by Formula 1:

[0015] [ka]

[0016] In the above Chemical Formula 1, L1 and L2 are the same or different and each independently represent a direct bond; a substituted or unsubstituted alkylene group having 1 to 4 carbon atoms; or a substituted or unsubstituted arylene group having 6 to 30 carbon atoms; A is hydrogen or a substituted or unsubstituted alkyl group having 1 to 3 carbon atoms; n is an integer from 0 to 4, Among R1 to R3, two groups are the same or different and each independently represents a substituted or unsubstituted alkyl group having 1 to 4 carbon atoms, and the remaining group is a substituted or unsubstituted alkyl group having 3 to 20 carbon atoms; When n is 2 or more, two or more As are the same or different, X - is a hydroxy-based anion, a carbonate-based anion, a citrate-based anion, a cyanate-based anion, a phosphate-based anion, a benzoate-based anion, a sulfonate-based anion, a borate-based anion, a salicylate-based anion, a sulfonamide-based anion, or a sulfonimide-based anion.

[0017] According to one embodiment of the present invention, the X -may be an anion selected from trifluoromethanesulfonate, p-toluenesulfonate, tetrafluoroborate, thiocyanate, hexafluorophosphate, salicylate, hydroxybenzoate, carboxyphenolate, trifluoromethylsulfonamidate, trifluoromethanesulfonimidate, bistrifluoromethylsulfonamidate, or bis(trifluoromethyl)sulfonimidate.

[0018] According to one embodiment of the present invention, L1 and L2 may be the same or different and each independently represent a direct bond; or a substituted or unsubstituted alkylene group having 1 to 4 carbon atoms.

[0019] According to one embodiment of the present invention, L1 may be a direct bond; a methylene group or an ethylene group.

[0020] According to one embodiment of the present invention, L1 may be a methylene group.

[0021] According to one embodiment of the present invention, L1 may be a direct bond.

[0022] According to one embodiment of the present invention, L2 may be a direct bond; a methylene group; or an ethylene group.

[0023] According to one embodiment of the present invention, L2 may be a methylene group.

[0024] According to one embodiment of the present invention, L2 may be a direct bond.

[0025] According to one embodiment of the present invention, A may be all hydrogen.

[0026] According to one embodiment of the present invention, two of R1 to R3 may be the same or different and each independently represent a methyl group or an ethyl group, and the remaining group may be an unsubstituted alkyl group having 8 to 20 carbon atoms.

[0027] According to one embodiment of the present invention, the formula 1 may be represented by any of the following structures:

[0028] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka]

[0029] According to one embodiment of the present invention, the antibacterial composition may have a primary thermal decomposition temperature of 200° C. or higher.

[0030] In the present invention, the thermal decomposition temperature can be measured using a thermogravimetric analyzer.

[0031] The primary pyrolysis temperature can be defined as the extrapolated intersection point between the baseline of the initial mass and the tangent line of the maximum slope point in the initial mass loss section of a mass loss curve measured using a thermogravimetric analyzer in an N2 atmosphere.

[0032] In the present invention, the antibacterial composition is considered to have increased heat resistance when its primary thermal decomposition temperature is higher than that of the unsubstituted substance. However, when considering the processing and melting process of a polymer using the compound, the primary thermal decomposition temperature must be 200°C or higher to be considered to have thermal stability.

[0033] As long as the primary thermal decomposition temperature of the antibacterial composition is 200° C. or higher, there is no particular upper limit to the temperature, and the higher the temperature, the better the heat resistance.

[0034] As used herein, the primary thermal decomposition temperature is the temperature at which thermal decomposition occurs at the quaternary ammonium group of the compound, and the inventors have defined the primary thermal decomposition temperature as the temperature at which thermal decomposition occurs at the anionic group (i.e., X - ) and discovered that when quaternary ammonium groups are substituted with specific anions other than halogen anions, the thermal stability of the quaternary ammonium group increases, resulting in an increase in the thermal decomposition temperature. However, since secondary and subsequent thermal decompositions occur at sites other than the quaternary ammonium group, the primary thermal decomposition experiment was used as the basis, as it is easier to compare the effects under the same conditions.

[0035] Furthermore, the higher the thermal decomposition temperature of the quaternary ammonium compound (i.e., monomer) substituted with the specific anion, the more resistant the polymer containing it is to processes in high temperature environments.

[0036] According to one embodiment of the present invention, the antibacterial composition may have a bacterial growth inhibition rate of 70% or more against at least one strain of Gram-positive bacteria, Gram-negative bacteria, and fungi, as measured by the following method 1.

[0037] [Method 1] 0.04 g of the antibacterial composition was added to 20 mL of nutrient broth culture solution inoculated with 3,000±300 CFU / mL of bacterial strain, and the mixture was cultured in a shaking incubator at 37°C for 24 hours. The culture solution of the experimental group was measured for absorbance at a wavelength of 600 nm using a UV / Vis spectrophotometer. 20 mL of nutrient broth culture solution inoculated with 3,000±300 CFU / mL of the bacterial strain was cultured at 37°C for 24 hours without adding the antibacterial composition, and the control culture solution was measured for absorbance at a wavelength of 600 nm using a UV / Vis spectrophotometer. The bacterial growth inhibition rate (%) of the test group was calculated from the absorbance of the test group and the absorbance of the control group according to the following equation 1.

[0038]

number

[0039] According to one embodiment of the present invention, the bacterial growth inhibition rate of the compound according to Method 1 may be 50% or more, 60% or more, 70% or more, 80% or more, or 90% or more.

[0040] In the present invention, "having antibacterial properties" means that the bacterial growth inhibition rate (%) is 50% or more, 60% or more, preferably 70% or more, and more preferably 80% or more.

[0041] In the present invention, "having antibacterial properties" means that the bacterial growth inhibition rate (%) according to Method 1 is 70% or more, preferably 80% or more.

[0042] According to one embodiment of the present invention, the Gram-positive bacterium may be any one selected from the group consisting of Enterococcus faecalis, Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes, Enterococcus faecium, and Lactobacillus lactis, but is not limited thereto.

[0043] In this specification, the Gram-positive bacteria are a collective term for bacteria that stain purple when stained by the Gram staining method. The cell walls of Gram-positive bacteria are composed of multilayered peptidoglycan, and after staining with a basic dye such as crystal violet, they retain their purple color even when treated with ethanol without fading.

[0044] The Gram-negative bacterium may be any one selected from the group consisting of Proteus mirabilis, Escherichia coli, Salmonella typhi, Pseudomonas aeruginosa, Vibrio cholerae, and Enterobacter cloacae, but is not limited thereto.

[0045] As used herein, the term "Gram-negative bacteria" refers to bacteria that stain red when stained with Gram staining. These bacteria have a cell wall with a relatively small amount of peptidoglycan compared to Gram-positive bacteria, but instead have an outer membrane made of lipopolysaccharides, lipoproteins, and / or other complex polymeric substances.

[0046] According to one embodiment of the present invention, the fungus may be, but is not limited to, Candida albicans.

[0047] Since the above Gram-positive bacteria, Gram-negative bacteria, and fungal strains can not only cause various diseases upon contact but also secondary infections, it is preferable to use a single antibacterial compound that exhibits antibacterial activity against all of the above Gram-positive bacteria, Gram-negative bacteria, and fungi.

[0048] In the present invention, when a member (layer) is said to be "on" another member (layer), this includes not only the case where a member (layer) is in contact with the other member, but also the case where another member (layer) exists between the two members (layers).

[0049] In the present invention, when a part "comprises" a certain component, this does not mean that it may exclude other components, but that it may further include other components, unless otherwise specified.

[0050] In the present invention, the term "monomer" refers to a unit compound, i.e., a monomer, that can be converted into a polymeric compound by a polymerization reaction, and the structure derived therefrom can become a repeating unit in a polymer or copolymer. Specifically, this means that when the compound is polymerized and bound to a polymer, all or part of two or more substituents in the compound structure are lost, and a radical for bonding to other units of the polymer is located in their place. In this case, the compound can be polymerized in any order and included in the polymer in a bound state. [Example]

[0051] Hereinafter, the present invention will be described in detail with reference to examples. However, the examples of the present invention can be modified into various other forms, and the scope of the present invention should not be construed as being limited to the examples described below. The examples of the present invention are provided to more completely explain the present invention to those skilled in the art.

[0052] Synthesis example: Synthesis of compounds. <Synthesis Example 1> The reaction scheme of the present invention is as follows:

[0053] [ka]

[0054] The compound (or antibacterial monomer) having a halogen anion used in the present invention was prepared as described above. A two-necked round-bottom flask-type reactor equipped with a stirrer and connected to a condenser and a stirrer was prepared. 50 g of 1-chloromethyl-4-vinyl benzene and 81.3 g of N,N-dimethyldodecyl amine were mixed with acetonitrile (150 mL) and then added to the reactor. After replacing the inside of the reactor with a nitrogen atmosphere, the temperature was raised to 45°C and the reaction was carried out with stirring for 24 hours or more. The solution after the reaction was completed was added dropwise to hexane, and the reactant was precipitated and purified. The purification process was repeated two more times, and the mixture was dried at about 80°C for 24 hours or more to obtain Compound 1. 1 For the H-NMR spectrum, see Figure 1.

[0055] <Synthesis Example 2> Compound 2 was produced in the same manner as in Synthesis Example 1, except that 81.3 g of N,N-dimethyldodecylamine was replaced with 56.7 g of N,N-dimethyloctylamine. 1 The synthesis was confirmed by 1 H-NMR spectrum.

[0056] <Synthesis Example 3> Compound 3 was produced in the same manner as in Synthesis Example 1, except that 81.3 g of N,N-dimethyldodecylamine was replaced with 69.0 g of N,N-dimethyldecylamine. 1 The synthesis was confirmed by 1 H-NMR spectrum.

[0057] <Synthesis Example 4> Compound 4 was produced in the same manner as in Synthesis Example 1, except that 81.3 g of N,N-dimethyldodecylamine was replaced with 105.9 g of N,N-dimethylcetylamine. 1 The synthesis was confirmed by 1 H-NMR spectrum.

[0058] <Synthesis Example 5> Compound 5 was produced in the same manner as in Synthesis Example 1, except that 81.3 g of N,N-dimethyldodecylamine was replaced with 130.6 g of N,N-dimethyl eicosanamine. 1 The synthesis was confirmed by 1 H-NMR spectrum.

[0059] Example: Anion Substitution (Preparation of Antibacterial Composition) Example 1 Compound 1 (1 g) prepared in Synthesis Example 1 was dissolved in 10 g of water. 0.94 g of sodium trifluoromethyl sulfonate was dissolved in 10 g of water in another vessel, and then added dropwise to the reactor. The mixture was stirred for 8 hours or more to convert anions from halogen anions (i.e., Cl). - ) Trifluoromethylsulfonate anion (CF3SO3 - ) was substituted with ethyl acetate. An excess amount of ethyl acetate was added to the substituted solution and mixed, and the mixed solution was left to stand for 30 minutes or more to separate the phases. After separating only the upper ethyl acetate from the separated mixed solution, magnesium sulfate (MgSO4) was added and the remaining water was removed. After filtering the magnesium sulfate in the ethyl acetate solution, the ethyl acetate was removed in a vacuum oven at 40°C, and the antibacterial composition of Example 1 was obtained. As shown in Figure 2, 19F-NMR (Nuclear Magnetic Resonance, Bruker, Ascend (trademark pending) 500) spectroscopy confirmed that the F element of trifluoromethyl sulfonate was detected, and the anion of Compound 1 in Synthesis Example 1 was Cl. - It was confirmed that the fluorine-containing trifluoromethylsulfonic acid was substituted with fluorine-containing trifluoromethylsulfonic acid.

[0060] <Example 2> The antibacterial composition of Example 2 was obtained in the same manner as in Example 1, except that compound 1 (1g) in Example 1 was replaced with compound 2 (1g) prepared in Synthesis Example 2. The antibacterial composition of Example 2 was obtained by the same method as in Example 1. 19 The anion substitution was confirmed by F-NMR spectroscopy.

[0061] Example 3 The antibacterial composition of Example 3 was obtained in the same manner as in Example 1, except that compound 1 (1g) in Example 1 was replaced with compound 3 (1g) prepared in Synthesis Example 3. The antibacterial composition of Example 3 was prepared by the same method as in Example 1. 19 The anion substitution was confirmed by F-NMR spectroscopy.

[0062] Example 4 The antibacterial composition of Example 4 was obtained in the same manner as in Example 1, except that compound 1 (1g) in Example 1 was replaced with compound 4 (1g) prepared in Synthesis Example 4. The antibacterial composition of Example 4 was prepared by the same method as in Example 1. 19 The anion substitution was confirmed by F-NMR spectroscopy.

[0063] <Example 5> The antibacterial composition of Example 5 was obtained in the same manner as in Example 1, except that 1 g of sodium trifluoromethyl sulfonate was replaced with 0.60 g of sodium tetrafluoroborate. 19The F-NMR spectroscopy results confirmed that the F element of tetrafluoroborate was detected, and it was confirmed that the anion of Compound 1 in Synthesis Example 1 was Cl. - It was confirmed that the fluorine-containing tetrafluoroboric acid was substituted with tetrafluoroboric acid.

[0064] Example 6 The antibacterial composition of Example 6 was obtained in the same manner as in Example 1, except that 1 g of sodium trifluoromethylsulfonate was replaced with 0.87 g of sodium salicylate. 19 F-NMR spectrum showed Cl - From F - When the substitution with salicylic acid (Salicylate) was confirmed, the F peak disappeared. - It was indirectly confirmed that the anion was substituted from methyl to salicylic acid.

[0065] Example 7 The antibacterial composition of Example 7 was obtained in the same manner as in Example 1, except that 1 g of sodium trifluoromethylsulfonate was replaced with 1.65 g of sodium bis(trifluoromethane)sulfonamide. 19 The anion substitution was confirmed by F-NMR spectroscopy.

[0066] Example 8 The compound of Example 8 was obtained in the same manner as in Example 1, except that 1 g of sodium trifluoromethylsulfonate was replaced with 0.65 g of sodium methane sulfonate. 19 F-NMR spectrum showed Cl - From F -When the substitution with methane sulfonate was confirmed, the F peak disappeared. - It was indirectly confirmed that the anion was substituted from methyl to methane sulfonate.

[0067] Example 9 The antibacterial composition of Example 9 was obtained in the same manner as in Example 1, except that 1 g of sodium trifluoromethylsulfonate was replaced with 0.79 g of sodium benzoate. 19 F-NMR spectrum showed Cl - From F - When the substitution with benzoic acid was confirmed, the F peak disappeared. - It was indirectly confirmed that the anion was substituted from benzoic acid to benzoate.

[0068] Example 10 The antibacterial composition of Example 10 was obtained in the same manner as in Example 1, except that 1 g of sodium trifluoromethylsulfonate was replaced with 1.41 g of sodium citrate monobasic. 19 F-NMR spectrum showed Cl - From F - When the substitution with dihydrogen citrate (citrate monobasic) was confirmed, the F peak disappeared. - It was indirectly confirmed that the anion was substituted from HCl to dihydrogen citrate.

[0069] Example 11 The antibacterial composition of Example 11 was obtained in the same manner as in Example 1, except that 1 g of sodium trifluoromethylsulfonate was replaced with 0.74 g of sodium trifluoroacetate. 19 The anion substitution was confirmed by F-NMR spectroscopy.

[0070] Example 12 The compound of Example 12 was obtained in the same manner as in Example 1, except that 1 g of sodium trifluoromethylsulfonate was replaced with 1.01 g of potassium hexafluorophosphate. 19 The anion substitution was confirmed by F-NMR spectroscopy.

[0071] Example 13 The antibacterial composition of Example 13 was obtained in the same manner as in Example 1, except that 1 g of sodium trifluoromethylsulfonate was replaced with 0.53 g of potassium thiocyanate. 19 F-NMR spectrum showed Cl - From F - When the substitution with thiocyanate was confirmed, the F peak disappeared. - It was indirectly confirmed that the anion is substituted by thiocyanate.

[0072] Example 14 The antibacterial composition of Example 14 was obtained in the same manner as in Example 1, except that 1 g of sodium trifluoromethylsulfonate was replaced with 1.06 g of sodium p-toluenesulfonate. 19 F-NMR spectrum showed Cl - From F- When the substitution with p-toluenesulfonate was confirmed, the F peak disappeared. - It was indirectly confirmed that the anion was substituted from toluene to p-toluenesulfonic acid.

[0073] <Comparative Example 1> As in the previous examples, Compound 1 in Synthesis Example 1, which is a compound without anion substitution, was selected as the compound in Comparative Example 1. According to Figure 2, 19 The F-NMR spectroscopy results confirmed that no F element was detected, and the anion (Cl) of Compound 1 in Synthesis Example 1 was - ) remains as it is.

[0074] Experimental example. <Experimental Example 1: Primary pyrolysis measurement experiment> To test the primary thermal decomposition temperatures of the antibacterial compositions of Examples 1 to 13 and Comparative Example 1, a thermogravimetric analyzer (TGA2, Mettler Toledo) was used.

[0075] In this experiment, the first thermal decomposition temperature was defined as the extrapolated intersection point between the baseline of the initial mass and the tangent line of the maximum slope point in the initial mass loss section in a mass loss curve measured using a thermogravimetric analyzer in an N2 atmosphere. In the present invention, when the first thermal decomposition temperature of the antibacterial composition is higher than the first thermal decomposition temperature of the material before anion substitution, it is determined that the heat resistance has increased. The measurement results are shown in Table 1 below.

[0076] <Experimental Example 2: Bacterial growth inhibition rate (%) measurement experiment> In this experiment, the bacterial growth inhibition rate was measured by the following method 1. E. coli was used. The measurement results are shown in Table 1 below.

[0077] [Method 1] 0.04 g of the antibacterial composition was added to 20 mL of nutrient broth culture solution inoculated with 3,000±300 CFU / mL of bacterial strain, and the mixture was cultured in a shaking incubator at 37°C for 24 hours. The culture solution of the experimental group was measured for absorbance at a wavelength of 600 nm using a UV / Vis spectrophotometer. 20 mL of nutrient broth culture solution inoculated with 3,000±300 CFU / mL of the bacterial strain was cultured at 37°C for 24 hours without adding the antibacterial composition, and the control culture solution was measured for absorbance at a wavelength of 600 nm using a UV / Vis spectrophotometer. The bacterial growth inhibition rate (%) of the test group was calculated from the absorbance of the test group and the absorbance of the control group according to the following equation 1.

[0078]

number

[0079] [Table 1]

[0080] According to Table 1, Examples 1 to 14 are antibacterial compositions in which anions other than halogens are substituted, and they exhibited a bacterial growth inhibition rate of 90% or more, maintaining high antibacterial activity, while at the same time showing high heat resistance with a primary thermal decomposition temperature of 200°C or higher. In contrast, Comparative Example 1, which contained halogen anions, maintained a high level of antibacterial activity but showed low heat resistance with a primary thermal decomposition temperature of 200°C or lower.

Claims

1. An antibacterial composition comprising a compound represented by Formula 1: 【Chemistry 1】 In the above Chemical Formula 1, L1 is a direct bond; L2 is a methylene group; A is hydrogen; n is an integer from 0 to 4, Among R1 to R3, two groups are the same or different and each independently represent a methyl group or an ethyl group, and the remaining group is an unsubstituted alkyl group having 8 to 20 carbon atoms; When n is 2 or more, two or more A's are the same or different, X － is trifluoromethanesulfonate, p-toluenesulfonate, tetrafluoroborate, thiocyanate, hexafluorophosphate, salicylate, hydroxybenzoate, carboxyphenolate, trifluoromethylsulfonamidate, trifluoromethanesulfonimidate, bistrifluoromethylsulfonamidate, or bis(trifluoromethyl)sulfonimidate.

2. The antimicrobial composition of claim 1, wherein Formula 1 is represented by any of the following structures: 【Chemistry 2】 【Transformation 3】 【Chemistry 4】 【Transformation 5】 【Transformation 6】 【Transformation 7】 【Transformation 8】 【Chemistry 9】

3. 2. The antimicrobial composition of claim 1, wherein the compound has a primary thermal decomposition temperature of 200°C or higher.

4. The antibacterial composition according to claim 1, wherein the compound has a bacterial growth inhibition rate of 70% or more against at least one strain of Gram-positive bacteria, Gram-negative bacteria, and fungi as measured by the following method 1: [Method 1] 0.04 g of the antibacterial composition was added to 20 mL of Nutrient broth culture solution inoculated with 3,000±300 CFU / mL of bacterial strain, and the mixture was cultured in a shaking incubator at 37°C for 24 hours. The culture solution of the experimental group was measured for absorbance at a wavelength of 600 nm using a UV / Vis spectrophotometer. 20 mL of Nutrient broth culture solution inoculated with 3,000±300 CFU / mL of the bacterial strain was cultured at 37°C for 24 hours without adding the antibacterial composition, and the control culture solution was measured for absorbance at a wavelength of 600 nm using a UV / Vis spectrophotometer. The bacterial growth inhibition rate (%) of the test group was calculated from the absorbance of the test group and the absorbance of the control group according to the following equation 1. [Equation 1]

5. 5. The antibacterial composition according to claim 4, wherein the Gram-positive bacterium is any one selected from the group consisting of Enterococcus faecalis, Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes, Enterococcus faecium, and Lactobacillus lactis.

6. 5. The antibacterial composition according to claim 4, wherein the Gram-negative bacterium is any one selected from the group consisting of Proteus mirabilis, Escherichia coli, Salmonella typhi, Pseudomonas aeruginosa, Vibrio cholerae, and Enterobacter cloacae.

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