CN111658668A - Functional antibacterial combined medicine and application - Google Patents

Abstract

The present invention provides a functional antibacterial combination medicine and application thereof. The combination medicine includes the following two components that exist independently: aminophenylboronic acid and chloroauric acid trihydrate, and the combination medicine does not contain surface activity agent. Aminophenylboronic acid is a kind of pharmaceutical intermediate. It is used as a reducing agent in the synthesis process to prepare antibacterial gold nanoparticles. Boric acid combines with polysaccharide on the surface of bacteria through cis-diol, changes the permeability of bacterial cell wall, leads to bacterial death, and has stronger bacterial targeting; aminophenylboronic acid and chloroauric acid are stable and easy to store, and the whole preparation process is simple Controllable, the prepared antibacterial gold nanoparticles have good dispersibility, and can realize industrial production.

Description

Functional antibacterial combination drug and its application

technical field

The invention belongs to the field of medicine, and relates to a functional antibacterial combined medicine with antibacterial effect and its application.

Background technique

Several diseases caused by bacterial infections are already one of the biggest health problems in the world, killing millions of people every year from bacterial infections. Gram-negative and Gram-positive bacteria can cause many types of infections. For example, E. coli can cause gastrointestinal and urinary tract infections; Klebsiella pneumoniae can cause liver abscesses; and Staphylococcus aureus can cause skin infections. Antibiotics have been widely used to treat a variety of infections since they were first developed in the 1920s. However, the widespread use and misuse of antibiotics has rapidly led to the emergence of bacterial resistance and a new social panic. Due to the growing clinical and market demand, the development of novel antimicrobial drugs is imminent. Due to their large specific surface area, high degree of surface functionalization, and unique physical and chemical properties, nanomaterials have been widely used in medical devices, safe cosmetics, burn dressings, water treatment, food preservation, etc. Gold nanoparticles have many unique properties, such as good biocompatibility, multivalent effect, easy functionalization and fast synthesis, on the premise of having the above excellent properties. Therefore, gold nanoparticles become potential targets for the development of novel antibiotics. Many studies have shown that gold nanoparticles have no antibacterial activity on their own, but exhibit effective antibacterial activity after being modified with functional groups such as thiols, amines, and phosphonic acid compounds. As a drug intermediate, aminophenylboronic acid combines with peptidoglycan on the surface of bacteria through the boric acid group, which improves the targeting of bacteria and improves the utilization rate; the amino group in the aniline group is reducible and can no longer use reducing agents. Under the circumstance, the chloroauric acid is rapidly reduced to realize the rapid preparation of gold nanoparticles. Based on the above considerations, the reduction of gold nanoparticles by aminophenylboronic acid is a suitable choice for the preparation of novel antibacterial agents.

Oral administration has become the most widely used route of administration due to its low risk of infection, simple management procedures, and the ability to effectively improve drug solubility and permeability. Wait. When taken orally, the drug can be absorbed through the lymph and pass through the gastrointestinal barrier, so that the bioavailability of the drug is improved. Pharmacokinetic parameters. Scholars at home and abroad have made some explorations in the preparation of oral antibacterial agents using existing drugs and their application in bacterial infection. At present, the prior art discloses a nano-sulfur-silver composite sol and a preparation method and application thereof. After adding sulfur powder into polyethylene glycol, silver nitrate is added to obtain a nano-sulfur-silver composite sol. However, the preparation reaction of this method requires high temperature and the nano-silver is unstable, which is highly toxic to the human body. The US FDA has clearly prohibited the use of nano-silver in medical applications, and my country's CFDA has also restricted nano-silver in the medical field. Therefore, it is of great significance to explore antibacterial agents with superior biocompatibility and low toxicity. The prior art discloses a compound spiramycin nanoemulsion oral liquid and a preparation method thereof, which can significantly improve the bioavailability and drug stability of spiramycin by oral administration, but the oral liquid has a wide particle size distribution and complex raw material components. , including: surfactant, co-surfactant, oil phase, spiramycin, trimethoprim and deionized water, of which the active ingredient does not exceed 10%. Therefore, it is of great significance to explore new antibacterial agents with excellent antibacterial properties, high utilization rate of raw materials, and convenient oral administration. The prior art also discloses dissolving ultrafiltration-spray-drying-molecular dispersion coating-hydration granulation-freeze-drying to produce a liposome combination drug, and provides a formula and a process for the molar ratio of the raw materials of each component of the liposome oral preparation , but the preparation process is complex, the components are diverse, the interaction between the components is not clear, and only known drugs can be used, and the generation of drug resistance cannot be avoided. Therefore, it is of great significance to explore oral antibacterial agents that can effectively treat multidrug-resistant bacterial infections.

SUMMARY OF THE INVENTION

Therefore, the purpose of the present invention is to overcome the defects in the prior art, and to provide a functional gold-functional antibacterial combination drug with antibacterial effect and its application. The functional gold nanoparticles of the present invention have broad-spectrum antibacterial activity, especially against multidrug-resistant bacteria, and can be used to prepare novel and effective antibacterial drugs. The composition of the medicine is simple, can be rapidly synthesized under the strong acid environment in the stomach, and can be administered orally.

Before describing the content of the present invention, the terms used herein are defined as follows:

The term "ABA" refers to: aminophenylboronic acid.

The term "2ABA" refers to: anthranilic acid.

The term "3ABA" refers to: m-aminophenylboronic acid.

The term "4ABA" refers to: p-aminophenylboronic acid.

The term "Au_4ABAe NPs" refers to gold nanoparticles formed by reducing chloroauric acid with p-aminophenylboronic acid under the condition of pH=2.

The term "Au_4ABAi NPs" refers to gold nanoparticles formed by mixing p-aminophenylboronic acid and chloroauric acid in a one-to-one ratio in the stomach.

In order to achieve the above object, the first aspect of the present invention provides a functional antibacterial combination medicine, the combination medicine includes the following two components that exist independently: aminophenylboronic acid and chloroauric acid trihydrate, and the combination The drug does not contain surfactants.

According to the combination medicine of the first aspect of the present invention, the aminophenylboronic acid is selected from one or more of the following: p-aminophenylboronic acid, m-aminophenylboronic acid, and o-aminophenylboronic acid.

According to the combination medicine according to the first aspect of the present invention, in the combination medicine, the molar ratio of the aminophenylboronic acid and chloroauric acid trihydrate is 1:0.1-100, preferably 1:0.2-5.

The drug combination according to the first aspect of the present invention, wherein the drug is an oral drug.

The drug combination according to the first aspect of the present invention, wherein the drug is a solid oral preparation or a liquid oral preparation.

Preferably, the solid oral dosage form is selected from one or more of the following: tablets, granules, capsules and dropping pills; and/or

The liquid oral preparation is a solution combination in which two components of aminophenylboronic acid and chloroauric acid trihydrate exist independently.

According to the combination medicine according to the first aspect of the present invention, the combination medicine further includes a pharmaceutically acceptable adjuvant.

Preferably, the pharmaceutically acceptable adjuvants are selected from one or more of the following: fillers, disintegrants and lubricants.

The second aspect of the present invention provides the application of the functional antibacterial combination drug described in the first aspect in the preparation of antibacterial products;

Preferably, the bacteria are selected from Escherichia coli and/or Pseudomonas aeruginosa.

In order to design an antibacterial nanomaterial that is convenient to use, in view of the infection problem of multidrug-resistant bacteria, the present invention designs and provides a low-cost, good biological safety and good curative effect against multidrug-resistant bacteria to reduce chloroauric acid to prepare gold. Nanoparticle antibacterial agents and can be used orally in the treatment of abdominal infections. The gold nanoparticles target the polysaccharide on the surface of bacteria, destroy the bacterial cell wall and increase the permeability of the cell membrane, resulting in bacterial death. In this work, the inventors prepared functional gold nanoparticle antibacterial and antibacterial agents by reducing chloroauric acid with aminophenylboronic acid (ABA ortho-2ABA, meta-3ABA, para-4ABA), targeting sensitive strains of Gram-negative bacteria and clinically isolated multidrug-resistant strains have good antibacterial effect. Aminophenylboronic acid contains two functional groups, boronic acid group and aniline group. The aniline group has reducibility, which can directly reduce chloroauric acid to gold nanoparticles without using a reducing agent, and stably connect the ligand molecules. On gold nanoparticles; the boronic acid group can target the polysaccharide on the bacterial surface, which increases the permeability of the cell membrane by destroying the bacterial cell wall, resulting in bacterial death. During oral use, aminophenylboronic acid and chloroauric acid in the stomach can quickly form antibacterial gold nanoparticles, which can reach the whole body through the blood circulation through the gastrointestinal barrier, which improves the bioavailability of the drug. Compared with existing methods for synthesizing gold nanoparticles, the gold nanoantibacterial particles are stable to extreme changes in temperature and pH. The synthesized antibacterial gold nanoparticles were negatively charged with excellent biocompatibility. The principle diagram of the design of the present invention is shown in FIG. 1 . The feasibility of oral treatment of intra-abdominal infection was further verified by a mouse infection model.

To achieve the purpose, the present invention adopts the following technical solutions:

According to the present invention, gold nanoparticles reduced by small molecules are provided as antibacterial agents, wherein the small molecules are derivatives of phenylboronic acid with high biological safety, for example, the substituent on the benzene ring is an amino group. The substituent positions are ortho, meta and para.

According to the synthesis method of the antibacterial agent of gold nanoparticles prepared by aminophenylboronic acid reducing chloroauric acid provided by the present invention, wherein, the ratio of chloroauric acid to aminophenylboronic acid during the synthesis of gold nanoparticles is 1:5-5:1( i.e. the molar mass ratio). The pH value of the synthesis conditions is 2 to 12, preferably, the pH value is 2 to 7. In order to better simulate the strong acid environment of the stomach, more preferably, the pH value is 2. The average particle size of the gold nanoparticles with antibacterial effect is below 50 nm. More preferably, it is 2-10 nm.

The aminophenylboronic acid selected by the present invention contains two functional groups, a boronic acid group and an aniline group, and the aniline group has reducibility, which can directly reduce chloroauric acid into gold nanoparticles without using a reducing agent, and convert the complex into gold nanoparticles. The bulk molecule is stably connected to the gold nanoparticles; the boronic acid group can target the polysaccharide on the surface of the bacteria, which can increase the permeability of the cell membrane by destroying the bacterial cell wall, resulting in the death of the bacteria and achieving the antibacterial effect.

The gold nanoparticles reduced by aminophenylboronic acid prepared by the method of the invention have excellent antibacterial properties and can resist multidrug-resistant bacteria. During oral use, aminophenylboronic acid and chloroauric acid in the stomach can quickly form antibacterial gold nanoparticles, which can reach the whole body through the blood circulation through the gastrointestinal barrier, which improves the bioavailability of the drug. Compared with existing methods for synthesizing gold nanoparticles, the gold nanoantibacterial particles are stable to extreme changes in temperature and pH. The synthesized antibacterial gold nanoparticles were negatively charged with excellent biocompatibility. It can be used to make tablets, oral liquids and capsules, and is an excellent antibacterial agent.

The functional antibacterial combination drug of the present invention can have but not limited to the following beneficial effects:

1. Aminophenylboronic acid is a kind of drug intermediate. It is used as a reducing agent in the synthesis process to prepare antibacterial gold nanoparticles. The method is simple, does not induce bacterial resistance, and has high biological safety;

2. Aminophenylboronic acid modified on the surface of gold nanoparticles combines with polysaccharide on the surface of bacteria through cis-diol, which changes the permeability of bacterial cell wall and leads to bacterial death, and has stronger bacterial targeting;

3. Aminophenylboronic acid and chloroauric acid are stable and easy to store, the whole preparation process is simple and controllable, the prepared antibacterial gold nanoparticles have good dispersibility, and can realize industrial production; the synthesis method is convenient and can not be limited by temperature, pH and rotation speed, Can be used orally. Compared with the prepared gold nanoparticle solution, the reagent stored in the raw material is more stable, without the phenomenon of coagulation, and can not use surfactant, and the composition is more pure.

Description of drawings

Hereinafter, embodiments of the present invention will be described in detail with reference to the accompanying drawings, wherein:

Figure 1 shows the schematic diagram of the present invention to design and synthesize aminophenylboronic acid to reduce chloroauric acid to prepare antibacterial gold nanoparticles and use it orally to treat abdominal infection.

Figure 2 shows the morphological characterization and antibacterial properties of gold nanoparticles modified with p-aminophenylboronic acid in Example 1.

Figure 3 shows the morphological characterization and antibacterial properties of gold nanoparticles modified with m-aminophenylboronic acid in Example 2.

Figure 4 shows the morphological characterization and antibacterial properties of gold nanoparticles modified with anthranilic acid in Example 3.

Figure 5 shows the morphological characterization and antibacterial properties of gold nanoparticles modified with p-aminophenylboronic acid under different pH conditions in Example 4.

Figure 6 shows the characterization of the antibacterial mechanism of the gold nanoparticles modified with p-aminophenylboronic acid under the condition of pH 2 in Example 4.

Figure 7 shows Example 4 p-aminophenylboronic acid, chloroauric acid and gold nanoparticles and biosafety characterization.

FIG. 8 shows the metabolism of gold nanoparticles in blood and different organs over time by oral administration of gold nanoparticles in the reduction of chloroauric acid by aminophenylboronic acid in Example 5. FIG.

Figure 9 shows the therapeutic effect of Example 5 aminophenylboronic acid reducing chloroauric acid orally using gold nanoparticles for intraperitoneal infection in mice and monitoring of mouse body weight.

Detailed ways

The present invention is further described below through specific examples, but it should be understood that these examples are only used for more detailed and specific description, and should not be construed as being used to limit the present invention in any form.

This section provides a general description of the materials and test methods used in the tests of the present invention. While many of the materials and methods of operation used for the purposes of the present invention are known in the art, the present invention is described in as much detail as possible. It is clear to those skilled in the art that, in the context, if not specifically stated, the materials and methods of operation used in the present invention are well known in the art.

The reagents and instruments used in the following examples are as follows: Reagents:

Chlorauric acid trihydrate, purchased from Sinopharm Chemical Reagent Co., Ltd.;

p-aminophenylboronic acid, m-aminophenylboronic acid, o-aminophenylboronic acid, purchased from Sigma;

Tween 80, purchased from Aladdin Biotechnology Co., Ltd.;

Dialysis bags, purchased from Solarbio;

Filter, purchased from Millipore.

instrument:

Transmission electron microscope, purchased from FEI company, USA, model Tecnai G2 20 S-TWIN;

Microplate reader, purchased from Tecan, model Tecan infinite M200;

UV-Vis absorption spectrum, purchased from Shimadzu, Japan, model UV2450.

Figure 1 is a flow chart of the synthetic method and therapeutic use. Described below by specific embodiments:

Example 1

This example is used to illustrate the preparation method of the functional gold nanoparticles of the present invention.

Proceed as follows:

(1) In a round-bottomed flask, add 0.05 mmol of chloroauric acid trihydrate (molecular weight 393.83, Sinopharm Chemical Reagent Co., Ltd.) and 30 mg of Tween 80 into 10 ml of deionized water. Under different reaction conditions (rotation speed: 1000 rpm, 500 rpm and 100 rpm; temperature: 0 degrees Celsius and 25 degrees Celsius), 0.05 mmol of p-aminophenylboronic acid (4ABA molecular weight 136.941, Sigma) was added dropwise. ) solution of 1 ml, the color of the solution in the bottle immediately turned brown, and the reaction conditions were maintained for another 2 hours.

(2) The obtained p-aminophenylboronic acid-reduced gold nanoparticles were dialyzed with a dialysis bag (14 kDa MW cut-off, Solarbio) for 24 hours to remove untreated chemicals. The nanoparticles were sterilized by filtration through a 0.22 micron filter (Millipore) and stored in a refrigerator at 4°C until use. The morphology of the gold particles was characterized by transmission electron microscopy (TEM, Tecnai G220 S-TWIN, FEI company, USA), and the observation results are shown in FIG. 2A . The UV-Vis absorption spectrum (UV-Vis) test results of the samples are shown in Figure 2B.

(3) Escherichia coli (E.coli) and multidrug-resistant Escherichia coli (MDR E.coli) were cultured in liquid bacterial culture medium. The gold nanoparticles were diluted 2-128 times and then added to the medium with bacteria, and the inoculation concentration was 1×10 ⁴ CFU/mL. After culturing at 37°C for 12 hours and 24 hours, the bacterial suspension was tested for turbidity at 600nm. (OD _600nm ) to analyze the antibacterial activity of gold nanoparticles, the results are shown in Figure 2C.

Example 2

This example is used to illustrate the preparation method of the functional gold nanoparticles of the present invention.

Proceed as follows:

(1) In a round-bottomed flask, add 0.05 mmol of chloroauric acid trihydrate (molecular weight 393.83, Sinopharm Chemical Reagent Co., Ltd.) and 30 mg of Tween 80 into 10 ml of deionized water. Under different reaction conditions (rotational speed: 1000 rpm, 500 rpm and 100 rpm; temperature: 0°C and 25°C), 0.05 mmol of m-aminophenylboronic acid (3ABA molecular weight 136.941, Sigma) was added dropwise. ) solution of 1 ml, the color of the solution in the bottle immediately turned brown, and the reaction conditions were maintained for another 2 hours.

(2) The treatment and particle characterization of the gold nanoparticles reduced by m-aminophenylboronic acid are the same as in Example 1, and the results are shown in Figures 3A-B.

(3) The antibacterial activity characterization of the gold nanoparticles reduced by m-aminophenylboronic acid is the same as that in Example 1, and the results are shown in Figure 3C.

Example 3

This example is used to illustrate the preparation method of the functional gold nanoparticles of the present invention.

Proceed as follows:

(1) In a round-bottomed flask, add 0.05 mmol of chloroauric acid trihydrate (molecular weight 393.83, Sinopharm Chemical Reagent Co., Ltd.) and 30 mg of Tween 80 into 10 ml of deionized water. Under different reaction conditions (rotation speed: 1000 rpm, 500 rpm and 100 rpm; temperature: 0 degrees Celsius and 25 degrees Celsius), 0.05 mmol of anthranilic acid (2ABA molecular weight 136.941, Sigma) was added dropwise. ) solution of 1 ml, the color of the solution in the bottle immediately turned brown, and the reaction conditions were maintained for another 2 hours.

(2) The treatment and particle characterization of the gold nanoparticles reduced by anthranilic acid are the same as in Example 1, and the results are shown in Figures 4A-B.

(3) The antibacterial activity characterization of the gold nanoparticles reduced by anthranilic acid is the same as that in Example 1, and the results are shown in Fig. 4C.

Example 4

This example is used to illustrate the preparation method and performance evaluation of the functional gold nanoparticles of the present invention.

Proceed as follows:

(1) Use hydrochloric acid to prepare 10 mL of solutions with pH values of 2 and 4; use sodium hydroxide to prepare 10 mL of solutions with pH values of 10 and 12; use 10 mL of deionized water as the solution with pH value of 7.

(2) p-aminophenylboronic acid was added to solutions with different pH values to prepare 1 ml of a solution containing 0.05 mmol of aminophenylboronic acid.

(3) The prepared solutions of p-aminophenylboronic acid with different pH values were added to the solution of 0.05 mmol of chloroauric acid trihydrate (molecular weight 393.83, Sinopharm Chemical Reagent Co., Ltd.), and shaken 2-3 times. The color of the solution immediately turned brown, and the synthesized gold nanoparticles at different pH levels could be obtained. The reaction feeding sequence and feeding mode have no influence on the product. (4) The treatment and particle characterization of gold nanoparticles reduced by p-aminophenylboronic acid in different acid-base environments are the same as in Example 1, and the results are shown in Figures 5A-B.

(5) The antibacterial activity of gold nanoparticles reduced by p-aminophenylboronic acid in different acid-base environments is the same as that in Example 1. Compared with levofloxacin, the antibacterial effect of gold nanoparticles is more effective in treating multidrug-resistant bacteria , the results are shown in Fig. 5C-D. The stomach is a strong acid environment. In order to better simulate the environment in the body, the inventors used the gold nanoparticles (Au_ABAe NPs) reduced by p-aminophenylboronic acid under the condition of pH=2 to explore the antibacterial mechanism and biosafety . The inventors mixed bacteria (sensitive strains of Escherichia coli (E.coli) and Pseudomonas aeruginosa (P.a) and multidrug-resistant strains (MDR E.coli, MDR P.a)) with different concentrations of gold nanoparticles under shaking The bed was shaken at 260 rpm for 4 hours. The bacteria were centrifuged, fixed, dehydrated, and cut into ultra-thin sections, which were observed by scanning and transmission electron microscopy. The results are shown in Figure 6A-B.

(6) For further clinical application, the inventors tested different concentrations of gold nanoparticles and raw materials for synthesizing gold nanoparticles ( _para The hemolytic properties of phenylboronic acid (4ABA) and chloroauric acid (HAuCl ₄ )), using saline as a negative control and water as a positive control, the results are shown in Figure 7A. The in vitro cytotoxicity of mouse fibroblast (3T3) cells was assessed by testing their viability under different sample treatments, and the results are shown in Figure 7B.

Example 5

Proceed as follows:

(1) p-aminophenylboronic acid (4ABA) was prepared into a 0.05 mmol solution, and chloroauric acid trihydrate was prepared into a 0.05 mmol solution. (2) p-aminophenylboronic acid (4ABA) and chloroauric acid (HAuCl ₄ ) were injected into mice by gavage according to different volume ratios to explore the synthesis and metabolism of the two components in vivo. In Example 4, when the pH was 2, the metabolism of the gold nanoparticles synthesized in vitro was used as a reference. Mice were randomly divided into 4 groups (n=5) for gavage experiment, group 1 (4ABA and HAuCl ₄ gavage volume was 150 μl: 50 μl (3: 1)); group 2 (4ABA and HAuCl ₄ The gavage volume was 100 μl: 100 μl (1:1) Au_4ABAi NPs); group 3 (4ABA and HAuCl ₄ gavage volume was 50 μl: 150 μl (1:3)); group 4 (in vitro simulation Gold nanoparticles (Au_4ABAe NPs) synthesized in the stomach environment. The particles are gold nanoparticles synthesized in Example 4. Under the condition of pH 2, the raw material ratio is 0.05 mmol p-aminophenylboronic acid and 0.05 mmol gold chloride Acid-synthesized gold nanoparticles.

(3) Orbital blood was collected and dissected to obtain stomach, liver, spleen and kidney of mice after gavage at different time points (1, 2, 6, 12, 18, 24, 48 and 72 hours); blood and The organs were nitrified with aqua regia (nitric acid: hydrochloric acid 1:3), and the content of gold nanoparticles in each organ was analyzed using an inductively coupled plasma analyzer (ICP, iCAP 6300, Thermo Scientific, USA). The results are shown in Fig. 8A-D, the initial stage of synthesis of _4ABA and HAuCl4 in the stomach reaches the maximum value with different volume ratios, which proves the feasibility of oral administration; the plasma concentration-time curve shows that the concentration of gold atoms in blood is administered intragastrically. It increased rapidly after 6 hours and decreased within 24 hours. The gold concentration in kidney and liver dropped to zero after 72 hours, indicating a high clearance efficiency. Compared with the individual organ levels in Au_4ABAe NPs, group 2 showed the most similar trend.

(4) Use the ratio of group 2 to explore the antibacterial effect of orally administered gold nanoparticles in a mouse model of acute peritonitis. Sensitive strains (E.coli) and multidrug-resistant strains (MDR E.coli) of bacteria in exponential phase were injected into the abdominal cavity of mice at a concentration of 1×10 ⁶ CFU/mL. At 1 hour and 6 hours after infection, 100 μl each of 5 mmol/L 4ABA and 5 mmol/L HAuCl ₄ were administered by gavage, sterile saline was used as a negative control, and levofloxacin was used as a positive control, and the mortality of mice And mouse body weight monitoring is shown in Figure 9. As shown, it shows that when 4ABA and HAuCl ₄ are used orally, the treatment of intra-abdominal infection caused by multidrug-resistant bacteria is more effective than the commonly used antibiotic levofloxacin.

Although this invention has been described to a certain extent, it will be apparent that suitable changes in various conditions may be made without departing from the spirit and scope of the invention. It is to be understood that the invention is not limited to the embodiments described, but is to be included within the scope of the claims, which include equivalents for each of the elements described.

Claims (10)

1. a functional antibacterial combination medicine, it is characterised in that the combination medicine comprises the following two components that exist independently: aminophenylboronic acid and chloroauric acid trihydrate, and the combination medicine does not contain a surfactant . 2 . The combination medicine according to claim 1 , wherein the aminophenylboronic acid is selected from one or more of the following: p-aminophenylboronic acid, m-aminophenylboronic acid, and o-aminophenylboronic acid. 3 . 3. The combination medicine according to claim 1 or 2, wherein, in the combination medicine, the molar ratio of the aminophenylboronic acid and chloroauric acid trihydrate is 1:0.1～100, preferably 1:0.2 ~5. 4. The combination medicine according to any one of claims 1 to 3, wherein the medicine is an oral medicine. 5. The combination medicine according to any one of claims 1 to 4, wherein the medicine is a solid oral preparation or a liquid oral preparation. 6. combination medicine according to claim 5 is characterized in that: The solid oral dosage form is selected from one or more of the following: tablets, granules, capsules and dropping pills; and/or The liquid oral preparation is a solution combination in which two components of aminophenylboronic acid and chloroauric acid trihydrate exist independently. 7. The combination drug according to any one of claims 1 to 5, characterized in that, the combination drug further comprises a pharmaceutically acceptable adjuvant. 8. The drug combination according to claim 7, wherein the pharmaceutically acceptable adjuvant is selected from one or more of the following: filler, disintegrant and lubricant. 9. The application of the functional antibacterial combination drug according to any one of claims 1 to 8 in the preparation of antibacterial products. 10. The application according to claim 9, wherein the bacteria are selected from Escherichia coli and/or Pseudomonas aeruginosa.

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