CN115337296A - Composite material for inhibiting horizontal transfer of drug-resistant plasmid and preparation method and application thereof - Google Patents
Composite material for inhibiting horizontal transfer of drug-resistant plasmid and preparation method and application thereof Download PDFInfo
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- CN115337296A CN115337296A CN202210766494.9A CN202210766494A CN115337296A CN 115337296 A CN115337296 A CN 115337296A CN 202210766494 A CN202210766494 A CN 202210766494A CN 115337296 A CN115337296 A CN 115337296A
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
- A61K31/201—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids having one or two double bonds, e.g. oleic, linoleic acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
Abstract
The invention belongs to the technical field of biological materials, and particularly discloses a composite material for inhibiting horizontal transfer of drug-resistant plasmids, and a preparation method and application thereof. The invention provides a composite material for inhibiting horizontal transfer of drug-resistant plasmids, which can be used as a drug-resistant plasmid conjugation inhibitor, and the preparation steps of the composite material are as follows: s1, stirring and mixing castor oil and isophorone diisocyanate, sequentially adding piperazine and a catalyst, stirring for reaction, adding N-methyldiethanolamine, adding butanone when the solution is difficult to flow, cooling after the reaction, and neutralizing; s2, adding linoleic acid into the reaction system obtained in the step S1, adding water for emulsification, stirring and purifying to obtain the composite material. The composite material has pH response characteristics, can be administered to animal colon and caecum in a targeted mode, and can remarkably inhibit the conjugation and transfer of drug-resistant plasmids among bacteria in intestinal tracts; can be used as a novel effective plasmid inhibitor and provides a new method for the prevention and control of the horizontal transmission of plasmid-mediated drug-resistant genes.
Description
Technical Field
The invention relates to the technical field of biological materials, in particular to a composite material for inhibiting horizontal transfer of drug-resistant plasmids and a preparation method and application thereof.
Background
Antibiotic resistance is spreading rapidly worldwide, resistance gene transmission is mainly attributed to plasmid-mediated horizontal gene transmission, and many of the most problematic resistance problems today are associated with plasmid-mediated transmission of resistance genes. For example, a number of important drug resistance genes (bla) NDM Mcr-1,tet (X4), etc.) are mediated by plasmids and are widespread with plasmids. Animal knots and cecum are important places for the horizontal transfer of drug-resistant genes; the prevention and control of the horizontal transmission of drug resistance genes in the intestinal tract becomes a difficult problem.
Plasmid conjugation is a common mechanism for the horizontal transfer of bacterial drug resistance genes, and inhibition of plasmid conjugation is considered as one of the means to control the spread of bacterial drug resistance genes. The research shows that unsaturated fatty acid is considered as effective plasmid inhibitor (oleic acid, linoleic acid, 2-hexadecanoic and tanzawaic acids), so that the development and application of the novel plasmid inhibitor can become a new solution. Conjugation inhibitors will be used with antibiotics, or alone, to prevent resistance to or spread within pathogens. However, most of the current plasmid conjugation inhibitor research and development are carried out under in vitro experimental conditions, and the substance reports capable of inhibiting drug-resistant plasmid transmission in animal intestinal tracts are insufficient, so that the application of the plasmid conjugation inhibitor in clinical prevention and control of bacterial drug resistance is limited.
The waterborne Polyurethane (PU) has excellent adjustable performance and can be widely applied to the industries of coatings, adhesives, medical dressings and the like. In the medical community, polyurethanes have been widely used in drug responsive delivery systems for targeted release of drugs. The pH response type polyurethane is widely applied, can realize accurate drug delivery by targeting tumors, improves the treatment effect of the drug and reduces the toxic and side effects of the drug, but has no corresponding report on the propagation of bacterial drug resistance.
Disclosure of Invention
The invention aims to solve the problems and provides a composite material for inhibiting the horizontal transfer of drug-resistant plasmids and a preparation method and application thereof.
The first purpose of the invention is to provide a composite material for inhibiting the horizontal transfer of drug-resistant plasmids.
The second purpose of the invention is to provide the application of the composite material in preparing drug-resistant plasmid conjugation inhibiting drugs;
the composite material is prepared by the following method:
s1, stirring and mixing Castor Oil (CO) and isophorone diisocyanate (IPDI), sequentially adding piperazine and a catalyst, continuously stirring, then adding N-Methyldiethanolamine (MDEA), reacting until a solution is difficult to flow, adding butanone, continuously reacting, cooling, and then neutralizing;
s2, adding Linoleic Acid (LA) into the system obtained in the step S1, adding water for emulsification, stirring, and performing rotary evaporation on a product to obtain the composite material PULA (cationic polyurethane linoleic acid emulsion).
As a preferred technical solution of the present invention, the castor oil in step S1: piperazine: the mol ratio of N-methyldiethanolamine is 1:0.25: (0.89-1.19).
In a preferred embodiment of the present invention, in step S1, the catalyst is dibutyltin dilaurate (DBTDL), and the amount of the catalyst is 0.01 to 0.1%.
As a preferable technical scheme of the invention, the mass fraction of the linoleic acid in the step S1 is 3.33-3.39%.
As a preferred embodiment of the present invention, acetic acid is added for neutralization after cooling in step S1.
Preferably, the composite material in the above application is capable of inhibiting conjugative transfer of a drug-resistant plasmid in vivo.
Preferably, the drug-resistant plasmid conjugation inhibiting drug in the above application can be used for preventing and controlling bacterial drug resistance.
Compared with the prior art, the invention has the beneficial effects that:
(1) The invention provides a novel polyurethane linoleic acid composite material PULA, which is simple to prepare, high in biological safety and pH response characteristic, and can be administered in a targeted manner to animal nodules and cecum, so that the aim of accurate treatment is fulfilled.
(2) The PULA composite material provided by the invention can be used as a drug-resistant plasmid conjugation inhibitor, can obviously inhibit conjugation and transfer of IncX4 plasmid in vivo, and provides a new thought and method for overcoming bacterial drug resistance.
Drawings
FIG. 1 is a schematic diagram of the synthesis of PULA materials prepared according to the present invention.
FIG. 2 is a graph showing a particle size distribution of PULA prepared in examples of the present invention, FIG. 2A is a graph showing transmission microscope imaging results of the particle size distribution of PULA, and FIG. 2B is a graph showing measurement results of zeta sizer Nano-ZSE.
FIG. 3 is a pH responsive release profile of PULA prepared in accordance with the experimental examples of the present invention.
FIG. 4 is a graph showing HE staining of tissue sections of the PULA group and the control group prepared in example 2 of the present invention.
FIG. 5 is a graph showing the results of analyzing the conjugation and transfer of drug-resistant plasmid in PULA-inhibited mice prepared in example 2 of the present invention.
Detailed Description
The technical solutions of the present invention will be described clearly and completely below with reference to embodiments of the present invention, and it should be apparent that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
The experimental methods used in the examples of the present invention are all conventional methods unless otherwise specified; the materials, reagents and the like used are, unless otherwise specified, commercially available reagents and materials.
The invention relates to the material sources: LA from Shanghai Yien chemical technology, inc., CO from New bright-day trade, guangzhou, hep from Shanghai Aladdin Biochemical technology, inc., MDEA from Shanghai Yien chemical technology, inc., IPDI from Guangdong Wenjiang chemical reagent, inc., DBTDL from Shanghai Aladdin Biochemical technology, inc., and PBS from Beijing Lanjie Koch technology, inc.
Example 1
A composite material for inhibiting the horizontal transfer of drug-resistant plasmids is prepared by the following steps:
5.02g of Castor Oil (CO) and 4.42g of isophorone diisocyanate (IPDI) are weighed out and stirred in an oil bath at 78 ℃ for 10min with an electric stirrer (rotational speed 130-170 r/min) and 0.4g of piperazine (Hep) is added. Then 0.01% (10 μ L) of the catalyst dibutyltin dilaurate (DBTDL) was added and stirring was continued for 10min. Adding a certain amount of N-Methyldiethanolamine (MDEA), continuously stirring and reacting until the solution almost flows, adding 30ml of butanone, and continuously stirring for 2h at the temperature of 60-80 ℃. Stopping heating, adding appropriate amount of acetic acid for neutralization after the solution is cooled to room temperature, and stirring for 30min. 2.35g of Linoleic Acid (LA) is added into the reaction system, the speed is regulated to 300r/min, 90ml of deionized water is added for emulsification, and the mixture is stirred for 2 hours. Transferring the product to a single-neck round-bottom flask, and carrying out rotary evaporation at 40 ℃ for 30min to obtain the novel cationic polyurethane linoleic acid emulsion. Wherein the molar ratio of CO, hep and MDEA is 1:0.25:0.89.
example 2
A composite material for inhibiting horizontal transfer of drug-resistant plasmids is prepared by the following steps:
5.02g of Castor Oil (CO) and 4.42g of isophorone diisocyanate (IPDI) are weighed out in an oil bath at 78 ℃ for 10min with a motor stirrer (rotational speed 130-170 r/min) and 0.4g of piperazine (Hep) is added. Then 0.01% (10 μ L) of the catalyst dibutyltin dilaurate (DBTDL) was added and stirring was continued for 10min. Adding a proper amount of N-Methyldiethanolamine (MDEA), continuously stirring and reacting until the solution almost flows, adding 30ml of butanone, and continuously stirring for 2 hours at the temperature of 60-80 ℃. Stopping heating, cooling the solution to room temperature, adding appropriate amount of acetic acid for neutralization, and stirring for 30min. 2.35g of Linoleic Acid (LA) is added into the reaction system, the speed is regulated to 300r/min, 90ml of deionized water is added for emulsification, and the mixture is stirred for 2 hours. Transferring the product to a single-neck round-bottom flask, and carrying out rotary evaporation at 40 ℃ for 30min to obtain the novel cationic polyurethane linoleic acid emulsion. The molar ratio of CO, hep and MDEA is 1:0.25:0.99.
example 3
A composite material for inhibiting the horizontal transfer of drug-resistant plasmids is prepared by the following steps:
5.02g of Castor Oil (CO) and 4.42g of isophorone diisocyanate (IPDI) are weighed out in an oil bath at 78 ℃ for 10min with a motor stirrer (rotational speed 130-170 r/min) and 0.4g of piperazine (Hep) is added. Then 0.01% (10 μ L) of dibutyltin dilaurate (DBTDL) as a catalyst was added and stirring was continued for 10min. Adding a proper amount of N-Methyldiethanolamine (MDEA), continuously stirring and reacting until the solution almost flows still, adding 30ml of butanone, and continuously stirring at 60-80 ℃ for 2h. Stopping heating, adding appropriate amount of acetic acid for neutralization after the solution is cooled to room temperature, and stirring for 30min. 2.35g of Linoleic Acid (LA) is added into the reaction system, the speed is regulated to 300r/min, 90ml of deionized water is added for emulsification, and the mixture is stirred for 2 hours. Transferring the product to a single-neck round-bottom flask, and carrying out rotary evaporation at 40 ℃ for 30min to obtain the novel cationic polyurethane linoleic acid emulsion. The molar ratio of CO, hep and MDEA is 1:0.25:1.09.
example 4
A composite material for inhibiting horizontal transfer of drug-resistant plasmids is prepared by the following steps:
5.02g of Castor Oil (CO) and 4.42g of isophorone diisocyanate (IPDI) are weighed out in an oil bath at 78 ℃ for 10min with a motor stirrer (rotational speed 130-170 r/min) and 0.4g of piperazine (Hep) is added. Then 0.01% (10 μ L) of dibutyltin dilaurate (DBTDL) as a catalyst was added and stirring was continued for 10min. Adding a proper amount of N-Methyldiethanolamine (MDEA), continuously stirring and reacting until the solution almost flows still, adding 30ml of butanone, and continuously stirring at 60-80 ℃ for 2h. Stopping heating, cooling the solution to room temperature, adding appropriate amount of acetic acid for neutralization, and stirring for 30min. 2.35g of Linoleic Acid (LA) is added into the reaction system, the speed is regulated to 300r/min, 90ml of deionized water is added for emulsification, and the mixture is stirred for 2 hours. Transferring the product to a single-neck round-bottom flask, and carrying out rotary evaporation at 40 ℃ for 30min to obtain the novel cationic polyurethane linoleic acid emulsion. The molar ratio of CO, hep and MDEA is 1:0.25:1.19.
experimental example 1
Measurement of Loading Properties of composite PULA prepared in examples 1 to 4 of the present invention
The method for measuring the drug loading rate and the encapsulation efficiency comprises the following steps: filtering a certain amount of polyurethane emulsion through a 0.22 mu M syringe filter to remove unencapsulated insoluble linoleic acid, freeze-drying the emulsion, adding a certain amount of freeze-dried polyurethane (M) into acetonitrile, ultrasonically dissolving for 30-60min, centrifuging, and testing the concentration of supernatant by using HPLC (high performance liquid chromatography) to obtain the content (M) of the encapsulated linoleic acid. The actual dosage of the waterborne polyurethane emulsion is m 0 The drug Loading (LC) and the Encapsulation Efficiency (EE) were calculated by the following formulas:
drug Loading (LC)% = M/M × 100%
Encapsulation Efficiency (EE)% = m/m 0 ×100％
And (4) analyzing results:
the solid content, drug loading, and encapsulation efficiency of the composites prepared in examples 1-4 of the present invention are shown in table 1. Wherein PU 0.99 The solid content, the drug loading rate and the encapsulation rate of LA are higher.
TABLE 1
Experimental example 2
The particle diameter and Zeta potential of the composite PULA prepared in examples 1 to 4 of the present invention were measured
The test method comprises the following steps: the particle size and zeta potential of the aqueous polyurethane emulsion were characterized using a zeta sizer Nano-ZSE (malvern instrument) and the emulsion was diluted to about 0.01% by weight with distilled water before the test. The structure and particle size of the samples were further characterized using transmission electron microscopy.
And (4) analyzing results:
the Zeta potential results are shown in Table 2 and indicate that the 4 PULAs are cationic compounds and positively charged. The transmission microscope imaging results (see FIG. 2A) and the zeta sizer Nano-ZSE measurement results (see FIG. 2B) show that the particle sizes of the 4 PULAs are 50 to 500nm, and therefore, the 4 PULAs synthesized by the present invention are all Nano-scale materials.
TABLE 2
Experimental example 3
In vitro Release test of composite PULA prepared in examples 1 to 4 of the present invention at different pH
The test method comprises the following steps: solutions with pH values of 2,5.8 and 7.4 were prepared, respectively. 100mL of PBS buffer was placed in a capped jar and 3 replicates of each concentration gradient were performed. Respectively placing about 0.05g into dialysis bags of 2.5cm × 5cm, clamping both ends with clips, the test was carried out in 2,5.8,7 PBS solution (containing 0.2% Tween-80) on a shaker at a temperature of 37 ℃ and a rotation speed of 120 rpm/min. 2mL of buffer solution was taken at 0h,0.5,1,2,4,6,8, 10, 12, and 24, and 2mL of Na with the corresponding concentration was added after each taking 2 S solution, keeping the volume of the solution unchanged. The samples were taken out each time and stored in a refrigerator at-20 ℃. And after all the samples are taken out, carrying out pretreatment, and carrying out content test by using high performance liquid chromatography.
And (4) HPLC detection: and (3) establishing a standard curve by using the LA standard substance, measuring LA response polyurethane and in vitro release, and determining the concentration of the medicament according to the peak area of the standard curve.
And (4) analyzing results:
as shown in FIG. 3, the four polyurethane materials all have pH-responsive release characteristics, wherein PU is 0.99 -LA、PU 1.09 -LA、PU 1.19 LA responds better to the release. The emulsion has complete structure under acidic condition (pH 2.0), and outer membrane structure is destroyed under neutral and alkaline condition (pH 7.4) to release LA. The colon and the caecum of the animal are in weakly acidic and neutral environments (pH is 6.0-7.0), so the PULA provided by the invention can release LA in the colon and the caecum of the animal, and a basis is provided for inhibiting the conjugation and transfer of drug-resistant plasmids.
Experimental example 4
Cytotoxicity evaluation of composite PULA prepared in example 2 of the present invention
Respectively taking the experimental group and PU 0.99 Liver, kidney, spleen, stomach, duodenum, colon of LA group miceThe tissue is sized appropriately and stored in a vial containing a fixative solution.
The samples were sent to a bio-corporation for tissue section preparation and HE staining.
And (4) analyzing results:
as shown in FIG. 4, PU 0.99 Compared with the results of HE staining of tissue sections of the-LA group and the control group, the tissues of the liver, the kidney, the spleen, the stomach, the duodenum and the colon have no obvious lesions, which indicates that PU-LA has small influence on cell tissues.
Experimental example 5
Animal experiments: the composite material PULA prepared in example 2 of the present invention was selected for measurement in inhibiting conjugative transfer in vivo.
The method comprises the following specific steps:
1. preparation of bacterial suspension
Donor bacteria E.coli MQCSZ4GFP and E.coli C600-lux were cultured to the log phase of growth (OD) 600 About 0.3).
2. Animal experiment process
The invention provides a drug-resistant plasmid conjugation transfer model in mouse intestinal tract:
according to the invention, a C57B6/7 mouse with the age of 6-8 weeks is taken as a research object, and 200 mu L/streptomycin/day (the concentration is 5 g/L) of the mouse is continuously gavaged, so that the intestinal flora of the mouse is disturbed. Streptomycin was removed on the evening of day 4 after streptomycin administration and mice were fasted and water-deprived. Mice were gavaged with 200 μ L of a suspension of donor and recipient bacteria and 1h after challenge diet and water were restored. Collecting 0.1g of mouse feces/ mouse 1, 3, 5 and 7 days after bacteria attack, pretreating the feces, diluting and plating the feces on a selective culture medium by a multiple proportion, standing and culturing for 18-24 h at 37 ℃, counting the number of donor bacteria and acceptor bacteria and calculating the conjugation transfer frequency.
Conjugation transfer frequency = number of zygotes/number of recipient bacteria
The donor bacterium is E.coli MQCSZ4GFP constructed in the laboratory [ refer to patent CN110129246A ], carries a conjugative transfer IncX4 type plasmid, and can move a colistin drug resistance gene (mcr-1) on the plasmid.
The recipient bacterium E.coli C600-lux is a strain (refer to patent CN 110066820A) which is constructed in the earlier stage of the research and can emit light biologically, carries streptomycin drug resistance gene rpsl, and has high resistance to streptomycin sulfate.
The fecal pretreatment method is to accurately weigh 0.1g of mouse feces, add the mouse feces into 900 mu L of phosphate buffer solution, and uniformly mix the sample by oscillation.
The selective culture media are respectively Macconyya agar culture media (containing 2000 mug/mL streptomycin sulfate) and are used for screening and counting the number of the recipient bacteria; and mecnkia agar medium (containing 2000. Mu.g/mL streptomycin sulfate + 2. Mu.g/mL polymyxin E) intended for selection of plasmid zygotes.
The specific experimental operation steps are as follows: several mice were purchased in a sterile environment for adaptive feeding for 7 days, followed by streptomycin treatment for 3 days (1 mg/mouse/day). On the fourth day, the feed and purified water were removed, the donor and recipient suspensions were supplied on the fifth day, the feed and drinking water were re-supplied, and 30min later, purified water and PU prepared in example 2 of the present invention were supplied to the mice 0.99 LA emulsion, and continuous administration for seven days, as control group and test group (8 each), respectively, collecting 0.1g mouse feces/mouse each day, dissolving into 900 μ L PBS solution, performing gradient dilution, spreading the dilution to streptomycin sulfate medium containing 2000 μ g/mL, screening and counting the number of recipient bacteria; the plasmid conjugates were screened by plating on E MacConKa agar medium containing 2000. Mu.g/mL streptomycin sulfate + 2. Mu.g/mL polymyxin (see FIG. 5B).
And (4) analyzing results:
as shown in fig. 5, the control group of 8 mice detected plasmid zygotes in the feces of the first two days after challenge, where 5 plasmid zygote transfer events occurred on the first day after challenge. The next day after challenge, plasmid conjugative transfer events were found in 2 mice. While neither PULA group found a plasmid conjugative transfer event (see fig. 5A), indicating that PULA inhibited the occurrence of plasmid conjugative transfer (see fig. 5C).
It should be understood that the above-mentioned embodiments of the present invention are only examples for clearly illustrating the technical solutions of the present invention, and are not intended to limit the specific embodiments of the present invention. Any modification, equivalent replacement, and improvement made within the spirit and principle of the present invention claims should be included in the protection scope of the present invention claims.
Claims (7)
1. The application of a composite material in preparing a drug-resistant plasmid conjugation inhibiting drug is characterized in that the composite material is prepared by the following method:
s1, stirring and mixing castor oil and isophorone diisocyanate, sequentially adding piperazine and a catalyst, stirring for reaction, then adding N-methyldiethanolamine, adding butanone when the solution is difficult to flow, continuing the reaction, cooling, and then neutralizing;
s2, adding linoleic acid into the reaction system obtained in the step S1, adding water for emulsification, and purifying a product after stirring.
2. Use according to claim 1, wherein the castor oil of step S1: piperazine: the mol ratio of N-methyldiethanolamine is 1:0.25: (0.89-1.19).
3. The use of claim 1, wherein the catalyst of step S1 is dibutyltin dilaurate in an amount of 0.01 to 0.1%.
4. The use of claim 1, wherein the linoleic acid content in step S2 is 3.33-3.39% by weight.
5. Use according to claim 1, wherein acetic acid is added for neutralization after cooling in step S1.
6. The use according to claim 1, wherein the composite material is capable of inhibiting conjugative transfer of a drug-resistant plasmid in vivo.
7. The use of claim 1 or 6, wherein the drug-resistant plasmid conjugation inhibiting drug can be used to control bacterial drug resistance.
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